We evaluated the effect of adding clonidine to bupivacaine on postoperative pain control and oxygenation after intercostal nerve blockade (ICB) for thoracotomy, and attempted to distinguish a systemic from a local effect of clonidine. ICB with 2 mg/kg 0.5% bupivacaine was performed in 36 patients undergoing thoracotomy. Patients were randomized to one of three groups: 1) a control group that received bupivacaine with saline for ICB and an IM injection of saline, 2) an IM group that received bupivacaine with saline for ICB and an IM injection of 2 micrograms/kg clonidine, and 3) a block group that received bupivacaine with 2 micrograms/kg clonidine for ICB and an IM injection of saline. Blood gases, visual analog scale (VAS) scores, and analgesic demand were determined hourly for 8 h after arrival in the postoperative care unit (PCU). Patients in the block group had significantly lower VAS scores, higher arterial oxygen tension, and lower analgesic demand for the first 4 h in the PCU, compared with the two other groups. No difference was noted thereafter. We conclude that the addition of clonidine to bupivacaine for ICB leads to a short-term effect enhancing postoperative pain control and improving arterial oxygenation, probably mediated by a direct effect on the nerves. Implications: Severe pain after thoracotomy can lead to impaired ventilation. We studied the effect of adding clonidine to bupivacaine for intercostal nerve blockade after thoracotomy. Clonidine administered directly on the nerves enhanced analgesia and improved oxygenation for a short time compared with systemic administration or control.

Dimou et al 2003

Transdermal clonidine: does it affect pain after abdominal hysterectomy?

Dimou P, Paraskeva A, Papilas K, Fassoulaki A.

Acta Anaesthesiol Belg 2003;54(3):227–232.

Clonidine has analgesic properties. We evaluated the analgesic effect of clonidine perioperatively. Forty patients undergoing abdominal hysterectomy received randomly the evening before surgery transdermal clonidine covered with overlay (CLO group) or the overlay alone (CTL group). Ten min before induction they received i.v. clonidine 1 microgram.kg-1 (CLO) or normal saline (CTL). Induction was accomplished with fentanyl 5 micrograms.kg-1, thiopentone 5 mg.kg-1, cis-atracurium 0.15 mg.kg-1 and maintenance with sevoflurane 2% in 70% N2O. Hemodynamic parameters were recorded intraoperatively. Pain was assessed by VAS at rest and movement 2, 4, 6, 8, 24, 48, 72 h and 30 days, postoperatively. During the first 8 h postoperatively all patients received controlled analgesia with fentanyl followed by morphine i.m. 0.15 mg.kg-1 and paracetamol. From 24-72 h postoperatively, patients received 75 mg propoxyphene and 600 mg paracetamol i.m., on demand. Arterial blood pressure was lower in the CLO group 0, 3, 10 min after intubation. There was no difference in pain or fentanyl consumption 8 h postoperatively. The CLO group required less analgesics 24 h postoperatively (p = 0.023). The two groups did not differ in pain or analgesic requirements 72 h and 30 days postoperatively. Clonidine had a weak opioid sparing effect 24 h post-operatively, but did not affect pain in long term.

De Kock et al 1994

Intraoperative and postoperative analgesia using intravenous opioid, clonidine and lignocaine.

De Kock M, Lavandhomme P, Scholtes JL.

Anaesth Intensive Care 1994;22(1):15–21.

The postoperative analgesia afforded after colonic surgery by IV opioid, clonidine and lignocaine given intra- and postoperatively was evaluated. In a double-blind randomised trial, 80 male patients scheduled for colonic resection under general anaesthesia received fentanyl 5 micrograms.kg-1 at induction and another 4 micrograms.kg-1 before skin incision (group A) or fentanyl (same dose) plus clonidine 4 micrograms.kg-1 in 20 min + 2 micrograms.kg-1.h-1 (group B, C) or fentanyl plus clonidine (same dosage) plus lignocaine 2 mg.kg-1 before skin incision, repeated before peritoneal incision and retractor placement (group D). In the four groups, intraoperative boluses of fentanyl 2 micrograms.kg-1 were given in response to the painful stimulation of the procedure. Postoperative pain was managed with PCA delivering 2 mg morphine per request in group A, 1.5 mg morphine in group B, 1.5 mg morphine + 15 micrograms clonidine in group C and 1.2 mg morphine + 15 micrograms clonidine + 23 mg lignocaine in group D. Postoperative analgesia was assessed by recording the analgesic demands (met and unmet) and the dose of morphine delivered at 6, 12, 18, 24, 36 hours. Side-effects, pain and sedation analogue scores were also recorded. Analgesic demands and delivered morphine dose were reduced, at any time interval considered, in groups B, C, D, compared with A (P < 0.001). No differences were noted between the group B, C, D. Pain analogue scores were better in groups B, C, D compared with group A (P < 0.001). Sedation and side-effects were not increased in groups B, C, D.(ABSTRACT TRUNCATED AT 250 WORDS)

Esmaoglu et al 2005

Addition of dexmedetomidine to lidocaine for intravenous regional anaesthesia.

Esmaoglu A, Mizrak A, Akin A, Turk Y, Boyaci A.

Eur J Anaesthesiol 2005;22(6):447–51.

BACKGROUND AND OBJECTIVE: The aim of this study was to determine the duration of onset and regression time of sensory and motor blocks, the quality of anaesthesia and postoperative analgesia by the addition of dexmedetomidine to local anaesthetic solution in intravenous regional anaesthesia (IVRA). METHODS: Forty patients scheduled for elective hand surgery participated in this prospective randomized double-blind study. The IVRA was achieved using 3 mg kg(-1) lidocaine diluted with saline to a total volume of 40 mL in the control group or 1 microg kg(-1) of dexmedetomidine + 3 mg kg(-1) lidocaine diluted with saline to a total volume of 40 mL in the dexmedetomidine group. The onset and regression times for sensory and motor blocks were recorded. Qualities of anaesthesia, intraoperative and postoperative analgesic requirements were noted. RESULTS: There was no difference between the groups with respect to sensory and motor blocks onset and regression time. The quality of anaesthesia was better in the dexmedetomidine group than the control group and the difference was statistically significant. Intraoperative and postoperative analgesic requirements were greater in the control group than in the dexmedetomidine group. CONCLUSIONS: Addition of dexmedetomidine to local anaesthetic solution in IVRA improved the quality of anaesthesia and decreased analgesic requirements, but had no effect on the sensory and motor blocks onset and regression times.

Jacobson et al 1983

Extradural versus intramuscular diamorphine. A controlled study of analgesic and adverse effects in the postoperative period.

Jacobson L, Phillips PD, Hull CJ, Conacher ID.

Anaesthesia 1983;38(1):10–8.

The effects of diamorphine hydrochloride 0.1 mg/kg, given either extradurally or intramuscularly for postoperative analgesia were compared in two randomised double-blind studies involving 39 patients undergoing thoracotomy and major gynaecological surgery. Assessments were made at fixed intervals after the administration of diamorphine and consisted of the measurement of pain or analgesic effect. Segmental, sympathetic and any adverse effects were sought. There was no significant difference in the quality of analgesia between the two groups in either trial. Extradural diamorphine provided safe and effective analgesia of rapid onset, with no specific undesirable side-effects. In both studies, analgesia was more prolonged following extradural administration. The relative proportion of spinal binding may be increased after extradural administration and this may be reflected in the prolonged analgesia observed.

Bigler et al 1996

The effect of preoperative methylprednisolone on pulmonary function and pain after lung operations.

Bigler D, Jonsson T, Olsen J, Brenoe J, Sander-Jensen K.

Journal of Thoracic & Cardiovascular Surgery 1996;112(1):142–5.

Thirty-six patients undergoing elective thoracotomy with pulmonary resection with the use of combined epidural and general anesthesia were randomized into a double-blind study to receive a single intravenous preoperative dose of methylprednisolone 25 mg/kg body weight or a placebo (saline solution). Postoperative pain relief consisted of epidural morphine 4 mg and paracetamol 1 gm three times a day for 4 days. Postoperative pulmonary function (peak expiratory flow rate, forced expiratory volume in first second, forced vital capacity) was evaluated on days 1, 2, 3, 4, and 7 and after 1 month. The value obtained after 1 month served as the control value. Pain score at rest and during cough was evaluated after 4 and 8 hours and on days 1, 2, 3, and 4. Pulmonary function was reduced after operation to the same degree in the steroid and placebo group: 42% versus 41% for forced expiratory volume in first second and 38% versus 39% for forced vital capacity, compared with control values after 1 month. Pain score was reduced in the steroid group after 4 hours and on day 1 during rest and after 4 and 8 hours and on day 2 during cough, compared with results in the placebo group (p < 0.05). In the steroid group three patients underwent reoperation because of leakage through the chest wall incision. In conclusion, administration of a single preoperative dose of methylprednisolone did not affect the postoperative reduction in pulmonary function after thoracotomy despite attenuated pain response, and the results do not warrant steroid administration before lung operation.

Henzi et al 2000

Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review.

Henzi I, Walder B, Tramér MR.

Anesth Analg 2000;90:186–194.

The role of dexamethasone in the prevention of postoperative nausea and vomiting (PONV) is unclear. We reviewed efficacy and safety data of dexamethasone for prevention of PONV. A systematic search (MEDLINE, EMBASE, Cochrane Library, hand searching, bibliographies, all languages, up to April 1999) was done for full reports of randomized comparisons of dexamethasone with other antiemetics or placebo in surgical patients. Relevant end points were prevention of early PONV (0 to 6 h postoperatively), late PONV (0 to 24 h), and adverse effects. Data from 1,946 patients from 17 trials were analyzed: 598 received dexamethasone; 582 received ondansetron, granisetron, droperidol, metoclopramide, or perphenazine; 423 received a placebo; and 343 received a combination of dexamethasone with ondansetron or granisetron. With placebo, the incidence of early and late PONV was 35% and 50%, respectively. Sixteen different regimens of dexamethasone were tested, most frequently, 8 or 10 mg IV in adults, and 1 or 1.5 mg/kg IV in children. With these doses, the number needed to treat to prevent early and late vomiting compared with placebo in adults and children was 7.1 (95% CI 4.5 to 18), and 3.8 (2.9 to 5), respectively. In adults, the number needed to treat to prevent late nausea was 4.3 (2.3 to 26). The combination of dexamethasone with ondansetron or granisetron further decreased the risk of PONV; the number needed to treat to prevent late nausea and vomiting with the combined regimen compared with the 5-HT3 receptor antagonists alone was 7.7 (4.8 to 19) and 7.8 (4.1 to 66), respectively. There was a lack of data from comparisons with other antiemetics for sensible conclusions. There were no reports on dexamethasone-related adverse effects. IMPLICATIONS: When there is a high risk of postoperative nausea and vomiting, a single prophylactic dose of dexamethasone is antiemetic compared with placebo, without evidence of any clinically relevant toxicity in otherwise healthy patients. Late efficacy seems to be most pronounced. It is very likely that the best prophylaxis of postoperative nausea and vomiting currently available is achieved by combining dexamethasone with a 5-HT3 receptor antagonist. Optimal doses of this combination need to be identified.

SUMMARY: OBJECTIVE To determine the effects of preoperative dexamethasone on surgical outcome after laparoscopic cholecystectomy (LC).SUMMARY BACKGROUND DATA Pain and fatigue are dominating symptoms after LC and may prolong convalescence.METHODS In a double-blind, placebo-controlled study, 88 patients were randomized to intravenous dexamethasone (8 mg) or placebo 90 minutes before LC. Patients received a similar standardized anesthetic, surgical, and multimodal analgesic treatment. All patients were recommended 2 days postoperative duration of convalescence. The primary endpoints were fatigue and pain. Preoperatively and at several times during the first 24 postoperative hours, we measured C-reactive protein (CRP) and pulmonary function, pain scores, nausea, and number of vomiting episodes were registered. Analgesic and antiemetic requirements were recorded. Also, on a daily basis, patients reported scores of fatigue and pain before and during the first postoperative week and the dates for resumption of work and recreational activities.RESULTS Eight patients were excluded from the study, leaving 40 patients in each study group for analysis. There were no apparent side effects of the study drug. Dexamethasone significantly reduced postoperative levels of CRP (P = 0.01), fatigue (P = 0.01), overall pain, and incisional pain during the first 24 postoperative hours (P < 0.05) and total requirements of opioids (P < 0.05). In addition, cumulated overall and visceral pain scores during the first postoperative week were significantly reduced (P < 0.05). Dexamethasone also reduced nausea and vomiting on the day of operation (P < 0.05). Resumption of recreational activities was significantly faster in the dexamethasone group versus placebo group (median 1 day versus 2 days) (P < 0.05).CONCLUSION Preoperative dexamethasone (8 mg) reduced pain, fatigue, nausea and vomiting, and duration of convalescence in patients undergoing noncomplicated LC, when compared with placebo, and is recommended for routine use.

Romundstad et al 2004

Methylprednisolone intravenously 1 day after surgery has sustained analgesic and opioid-sparing effects.

Romundstad L, Breivik H, Niemi G, Helle A, Stubhaug A.

Acta Anaesthesiol Scand 2004;48(10):1223–31.

BACKGROUND: In previous studies on glucocorticoids for postoperative pain, the test drug has been given perioperatively, usually before measurement of baseline pain. In order to evaluate the time course and magnitude of the analgesic effect of a glucocorticoid in well-established postoperative pain, we compared methylprednisolone with ketorolac and placebo, after assessment of baseline pain on the first postoperative day. METHODS: This was a double-blind, single dose, randomized, parallel comparison of intravenous (i.v.) methylprednisolone 125 mg, ketorolac 30 mg as an active control, and placebo in 75 patients with moderate to severe pain 1 day after orthopaedic surgery. Outcome variables were pain intensity (0-100 VAS), pain relief (0-4 PAR) and rescue opioid consumption. RESULTS: Methylprednisolone was not significantly different from ketorolac and gave significantly lower pain intensity from 1 h (0-6 h, P < 0.02), and more pain relief 2-6 h after test drugs (P < 0.05) compared with placebo. After 24 h, pain intensity was lower in both active drug groups compared with placebo (methylprednisolone, P < 0.0001; ketorolac, P < 0.007). Number needed to treat (NNT) calculated from patients having more than at least 50% of maximum obtainable total pain relief during the first 6 h (>50%maxTOTPAR(6 h)) was 3.6 for methylprednisolone and 3.1 for ketorolac. Number needed to treat calculated from the percentage reporting at least 50% pain relief for at least 4 h (>50%PAR(4 h)) was 2.8 for both groups. Opioid consumption was significantly reduced for 72 h after methylprednisolone compared with ketorolac (P < 0.02) and placebo (P < 0.003). CONCLUSION: Methylprednisolone 125 mg i.v. 1 day after surgery gave similar early reduction of pain as i.v. ketorolac 30 mg. Less pain than placebo 24 h after methylprednisolone, and lower opioid consumption for 72 h compared with ketorolac and placebo indicate sustained analgesic effects of methylprednisolone.

Murphy et al 1993

Indomethacin commenced before operation was compared with postoperative indomethacin administration for pain relief in patients after elective thoracic surgery. In addition to indomethacin, all patients received i.v. opioids titrated to their individual requirements. There was no significant difference between the two groups in quality of pain relief, in cumulative opioid requirement or in the incidence of adverse effects. The quality of pain relief compared well with previous similar studies using this technique.

Barden et al 2004

Single dose oral diclofenac for postoperative pain.

Barden J, Edwards J, Moore RA, McQuay HJ.

Cochrane Database Syst Rev 2004(2):CD004768.

BACKGROUND: Diclofenac is a benzene-acetic acid derivative that acts, like other NSAIDs, by inhibiting cyclo-oxygenase isoforms that mediate the body's production of the prostaglandins implicated in pain and inflammation. Diclofenac is widely available as a sodium or potassium salt. Diclofenac potassium tablets are known as 'immediate-release' diclofenac as absorption takes place in the gastrointestinal tract whereas 'delayed-release' (enteric-coated) diclofenac tablets resist dissolution until reaching the duodenum. An existing review showed that diclofenac was an effective treatment for acute postoperative pain but did not address the distinction between potassium and sodium salts due to lack of data. The aim of this update is to gather and add appropriate information published subsequently and, data permitting, examine any potential differences between the two different diclofenac formulations. OBJECTIVES: To assess single dose oral diclofenac for the treatment of acute postoperative pain and determine whether there are differences between the different formulations. SEARCH STRATEGY: We searched the Cochrane Library (Issue 2, 2003), MEDLINE (1966 to May 1996), EMBASE (1980 to 1996), Biological Abstracts (1985 to 2003), the Oxford Pain Relief Database (1950 to 1994), PubMed (1996 to 2003) and reference lists of articles. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled clinical trials of single dose, oral diclofenac sodium or diclofenac potassium for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for inclusion in the review, quality and extracted data. The area under the pain relief versus time curve was used to derive the proportion of patients prescribed diclofenac or placebo with at least 50% pain relief over four to six hours using validated equations. The number needed to treat (NNT) was calculated. Information on adverse effects was also collected. MAIN RESULTS: One additional trial was included and added to the six trials included in the original review. All seven trials provided data for quantitative analysis: 581 patients were treated with diclofenac and 364 were treated with placebo. The NNT for at least 50% relief over four to six hours with diclofenac 25 mg, 50 mg and 100 mg compared with placebo was 2.8 (95% CI 2.1 to 4.3), 2.3 (2.0 to 2.7) and 1.9 (1.6 to 2.2) respectively. Though higher doses produced lower (better) NNTs, statistical significance was not achieved. There was no significant difference between diclofenac 50 mg and placebo in the proportion of patients experiencing dizziness, headache, nausea or vomiting. The weighted median duration of analgesia was 2 hours for placebo, 6.7 hours for diclofenac 50 mg and 7.2 hours for diclofenac 100 mg. Sensitivity analyses for drug formulation, pain model, trial size and quality did not reveal any statistically significant differences. REVIEWERS' CONCLUSIONS: Oral diclofenac is an effective single-dose treatment for moderate to severe postoperative pain. There was no significant difference between diclofenac and placebo in the incidence of adverse effects, or between diclofenac sodium and potassium, different pain models, smaller and larger trials and trials of higher and lower quality.

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly combined with intravenous morphine patient-controlled analgesia to relieve postoperative pain. NSAIDs have a documented 30-50% sparing effect on morphine consumption. However, most of the studies have not demonstrated a decrease in morphine adverse effects. A meta-analysis of randomized controlled trials was performed to evaluate the risk of morphine adverse effects in patients treated with NSAIDs. Twenty-two prospective, randomized, double-blind studies including 2,307 patients were selected. NSAIDs decreased significantly postoperative nausea and vomiting by 30%, nausea alone by 12%, vomiting alone by 32% and sedation by 29%. A regression analysis yielded findings indicating that morphine consumption was positively correlated with the incidence of nausea and vomiting. Pruritus, urinary retention, and respiratory depression were not significantly decreased by NSAIDs.

BACKGROUND: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of ulcers and upper gastrointestinal (GI) ulcer complications, which has been attributed to the inhibition of cyclooxygenase-1. These risks are usually increased in elderly populations. Parecoxib sodium is an injectable prodrug of the cyclooxygenase-2-specific inhibitor valdecoxib that has exhibited analgesic activity in previous trials. OBJECTIVE: The purpose of this study was to compare the GI safety and tolerability profile of parecoxib sodium with that of ketorolac, naproxen, and placebo in a 7-day endoscopic trial in elderly subjects. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. After a normal baseline endoscopy, healthy elderly subjects aged 66 to 75 years were randomized to receive i.v. parecoxib sodium (10 mg BID), oral naproxen (500 mg BID), or placebo for 7 days, or placebo for 2 days followed by i.v. ketorolac (15 mg QID) for 5 days. Endoscopy was performed again after 7 days. RESULTS: Among the first 17 subjects enrolled, ulcers were observed in all treatment groups except the parecoxib sodium group (ketorolac, 4/4 subjects; naproxen, 2/4 subjects; and placebo, 2/5 subjects). Four subjects in the ketorolac group and 1 subject in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the unexpectedly high incidence of gastroduodenal ulcers observed, the study was terminated early and the randomization blind broken. CONCLUSION: These findings suggest that elderly patients may be at risk for GI ulceration even after short-term use of the conventional NSAIDs ketorolac and naproxen.

Greer et al 1999

Effect of ketorolac and low-molecular-weight heparin individually and in combination on haemostasis.

Greer I, Gibson J, Young A, Johnstone J, Walker I.

Blood Coagul Fibrinolysis 1999;10(6):367–373.

Low-molecular-weight heparins, when used in surgical patients for thromboprophylaxis, may be used concurrently with ketorolac, a non-steroidal anti-inflammatory drug that is used for analgesia. Because these two agents can influence the haemostatic system, it is important to identify any such effect. The haemostatic interaction between dalteparin and ketorolac was assessed in a double-blind, placebo-controlled, randomized, crossover study of healthy male volunteers each given all four combinations of ketorolac/placebo and dalteparin/placebo. The effect of ketorolac and dalteparin on haemostasis was assessed by measuring in-vitro platelet aggregation, anti-factor-Xa, activated partial thromboplastin times and skin bleeding time. The results were analysed for evidence of an interaction between ketorolac and dalteparin. Ketorolac inhibited platelet aggregation in whole blood and platelet-rich plasma. The administration of dalteparin led to a significant increase in levels of anti-factor-Xa and a significant prolongation in the activated partial thromboplastin time, although it remained within the range of the normal population. There was no evidence of any interaction between ketorolac and dalteparin with regard to platelet aggregation, anti-factor-Xa activity or activated partial thromboplastin time. The administration of ketorolac significantly prolonged the skin bleeding time. There was a significant interaction between ketorolac and dalteparin to prolong the bleeding time, although dalteparin alone had no effect on bleeding time. There was an interaction between ketorolac and dalteparin, which affected bleeding times. Such an interaction raises the possibility of haemorrhagic complications developing perioperatively when these agents are used concomitantly. Further studies are required to examine the clinical importance of this interaction.

An et al 1991

Effects of hypotensive anesthesia, nonsteroidal antiinflammatory drugs, and polymethylmethacrylate on bleeding in total hip arthroplasty patients.

An HS, Mikhail WE, Jackson WT, Tolin B, Dodd GA.

J Arthroplasty 1991;6(3):245–250.

One hundred forty patients ranging in age from 26 to 88 years, who had primary total hip arthroplasty (performed by the same surgeon and lateral surgical approach), were analyzed for intraoperative and postoperative blood loss. The factors affecting blood loss, which include bleeding disorders, medications, duration of surgery, the mean intraoperative blood pressure, and use of cement, were all recorded. A significant reduction in the intraoperative blood loss was observed in the group of patients with hypotensive anesthesia (greater than 20 mmHg drop in the mean intraoperative blood pressure using inhalation anesthetics) compared to the group of patients who did not have hypotensive anesthesia. The patients who had been on aspirin or nonsteroidal antiinflammatory drugs prior to surgery had increased intraoperative and postoperative blood loss compared to the patients who did not take such medications. The effect of cementing with methylmethacrylate on bleeding was also observed; the patients with uncemented implants had a greater blood loss after operation than the patients who had cemented prosthetic components.

Niemi et al 1997

Comparison of the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers.

Niemi T, Taxell C, Rosenberg P.

Acta Anaesthesiol Scand 1997;41(10):1353–1358.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis which may result in impaired platelet function. Because NSAIDs have different abilities to inhibit cyclo-oxygenases we compared the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers. METHODS: Ten healthy male volunteers were given ketoprofen 1.4 mg/kg, ketorolac 0.4 mg/kg and diclofenac 1.1 mg/kg in saline i.v. on three different occasions, at more than one-week intervals, in a randomized double-blind crossover study. Platelet function was evaluated before (sample 0), 2 (sample 2) and 24 h (sample 3) after the beginning of the infusion. RESULTS: Two of the volunteers had no secondary platelet aggregation in their aggregation curves before the experiment (sample 0, studied three times) and their results were excluded from the final analysis. Diclofenac inhibited adrenaline (0.9 µg/ml) induced platelet aggregation less (median maximal aggregation 22.5%) than ketoprofen (18.3%) and ketorolac (15.7%) (p < 0.05) in sample 2. In the ketorolac group in sample 3 an impairment of adrenaline (0.9 µg/ml) induced platelet aggregation was still seen (26.7%) (p < 0.05) but not in the other groups. Diclofenac did not affect adenosine diphosphate (ADP) induced platelet aggregation. However, ketorolac caused an impairment in ADP (3 µM and 6 µM ) induced platelet aggregation and ketoprofen in ADP (6 µM ) induced platelet aggregation in sample 2. Bleeding time was prolonged (p < 0.05) after ketoprofen and ketorolac (sample 2) but not after diclofenac. Platelet retention on glass beads was unaffected by the tested drugs. CONCLUSION: Ketoprofen, ketorolac and diclofenac caused a reversible platelet dysfunction. Diclofenac had the mildest effect, while platelet dysfunction was still seen 24 h after the beginning of ketorolac.

Forrest et al 2002

Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery.

BACKGROUND: Ketorolac is approved for the relief of postoperative pain but concerns have been raised over a possible risk of serious adverse effects and death. Two regulatory reviews in Europe on the safety of ketorolac found the data were inconclusive and lacked comparison with other non-steroidal anti-inflammatory drugs. The aim of this study was to compare the risk of serious adverse effects with ketorolac vs diclofenac or ketoprofen in adult patients after elective major surgery. METHODS: This prospective, randomized multicentre trial evaluated the risks of death, increased surgical site bleeding, gastrointestinal bleeding, acute renal failure, and allergic reactions, with ketorolac vs diclofenac or ketoprofen administered according to their approved parenteral and oral dose and duration of treatment. Patients were followed for 30 days after surgery. RESULTS: A total of 11,245 patients completed the trial at 49 European hospitals. Of these, 5634 patients received ketorolac and 5611 patients received one of the comparators. 155 patients (1.38%) had a serious adverse outcome, with 19 deaths (0. 17%), 117 patients with surgical site bleeding (1.04%), 12 patients with allergic reactions (0.12%), 10 patients with acute renal failure (0.09%), and four patients with gastrointestinal bleeding (0.04%). There were no differences between ketorolac and ketoprofen or diclofenac. Postoperative anticoagulants increased the risk of surgical site bleeding equally with ketorolac (odds ratio=2.65, 95% CI=1.51-4.67) and the comparators (odds ratio=3.58, 95% CI=1.93-6.70). Other risk factors for serious adverse outcomes were age, ASA score, and some types of surgery (plastic/ear, nose and throat, gynaecology, and urology). CONCLUSION: We conclude that ketorolac is as safe as ketoprofen and diclofenac for the treatment of pain after major surgery.

Hegi et al 2004

Effect of rofecoxib on platelet aggregation and blood loss in gynaecological and breast surgery compared with diclofenac.

BACKGROUND: Non-selective cyclooxygenase (COX) inhibitors or non-steroidal anti- inflammatory drugs (NSAIDs) are frequently omitted for perioperative pain relief because of potential side-effects. COX-2-selective inhibitors may have a more favourable side-effect profile. This study tested the hypothesis that the COX-2-selective inhibitor rofecoxib has less influence on platelet function than the NSAID diclofenac in gynaecological surgery. In addition, analgesic efficacy and side-effects of the two drugs were compared. METHODS: In this single-centre, prospective, double-blind, active controlled study, women undergoing vaginal hysterectomy (n = 25) or breast surgery (n = 25) under general anaesthesia received preoperatively 50 mg of rofecoxib p.o. followed 8 and 16 h later by two doses of placebo or three doses of diclofenac 50 mg p.o. at the same time points. We assessed arachidonic acid-stimulated platelet aggregation before and 4 h after the first dose of study medication, estimated intraoperative blood loss, and haemoglobin loss until the first morning after surgery. Analgesic efficacy, use of rescue analgesics, and side-effects were also recorded. RESULTS: In the rofecoxib group, stimulated platelet aggregation was disturbed less (p = 0.02), and estimated intraoperative blood loss (p = 0.01) and the decrease in haemoglobin were lower (p = 0.01). At similar pain ratings, the use of anti-emetic drugs was less in the rofecoxib group (p = 0.03). CONCLUSION: Besides having a smaller effect on platelet aggregation, one oral dose of rofecoxib 50 mg given before surgery provided postoperative analgesia similar to that given by three doses of diclofenac 50 mg and was associated with less use of anti-emetics and less surgical blood loss in gynaecological surgery compared with diclofenac.

Stevenson 2004

Aspirin and NSAID sensitivity.

Stevenson DD.

Immunol Allergy Clin North Am 2004;24(3):491–505, vii.

Aspirin and the older nonsteroidal anti-inflammatory drugs (NSAIDs) that block cyclo-oxygenase-1 (COX-1) induce asthma attacks in patients with aspirin-exacerbated respiratory disease and urticaria in patients with chronic idiopathic urticaria. Weak inhibitors of COX-1, such as acetaminophen and salsalate, crossreact also but only with high doses of the drugs. Partial inhibitors of both COX-1 and COX-2, such as nimesulide and meloxicam, also cross-react but only at high drug doses. COX-2 inhibitors do not cross-react; however, all NSAIDs, including the selective COX-2 inhibitors, can sensitize patients and induce urticaria or anaphylaxis on next exposure to the drug.

O'Connor et al 2003

Hepatocellular damage from non-steroidal anti-inflammatory drugs.

O'Connor N, Dargan PI, Jones AL.

QJM 2003;96(11):787–791.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of rheumatological disorders, and as analgesics and antipyretics. Hepatotoxicity is an uncommon, but potentially lethal complication, which usually occurs within 12 weeks of starting therapy. It can occur with all NSAIDs, but appears to be more common with diclofenac and particularly sulindac. Female patients aged >50 years, with autoimmune disease, and those on other potentially hepatotoxic drugs, appear to be particularly susceptible. Liver function test abnormalities generally settle within 4-6 weeks of stopping the causative drug. However, some patients may develop acute liver failure and successful orthotopic liver transplantation may be undertaken in such patients. Recent in vitro animal studies have shown that the mechanism of diclofenac toxicity relates both to impairment of ATP synthesis by mitochondria, and to production of active metabolites, particularly n,5-dihydroxydiclofenac, which causes direct cytotoxicity. Mitochondrial permeability transition (MPT) has also been shown to be important in diclofenac-induced liver injury, resulting in generation of reactive oxygen species, mitochondrial swelling and oxidation of NADP and protein thiols. Physicians and hepatologists must be vigilant to the hepatotoxic potential of any NSAID, as increased awareness, surveillance and reporting of these events will lead to a better understanding of the risk factors and the pathophysiology of NSAID-related hepatotoxicity.

Cheng et al 2004

Cyclooxygenases, the kidney, and hypertension.

Cheng HF, Harris RC.

Hypertension 2004;43(3):525–530.

Selective cyclooxygenase (COX)-2 inhibitors that are in widespread clinical use were developed to avoid side effects of conventional NSAIDs, including gastrointestinal and renal toxicity. However, COX-2 is constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in maintenance of renal blood flow, mediation of renin release, and regulation of sodium excretion. COX-2 inhibition may transiently decrease urine sodium excretion in some subjects and induce mild to moderate elevation of blood pressure. Furthermore, in conditions of relative intravascular volume depletion and/or renal hypoperfusion, interference with COX-2 activity can have deleterious effects on maintenance of renal blood flow and glomerular filtration rate. In addition to physiological regulation of COX-2 expression in the kidney, increased renal cortical COX-2 expression is seen in experimental models associated with altered renal hemodynamics and progressive renal injury (decreased renal mass, poorly controlled diabetes), and long-term treatment with selective COX-2 inhibitors ameliorates functional and structural renal damage in these conditions.

Gajraj 2003

The effect of cyclooxygenase-2 inhibitors on bone healing.

Gajraj NM.

Reg Anesth Pain Med 2003;28(5):456–465.

Buvanendran et al 2003

Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial.

CONTEXT: Controlling postoperative pain after knee replacement while reducing opioid-induced adverse effects and improving outcomes remains an important challenge. OBJECTIVE: To assess the effect of combined preoperative and postoperative administration of a selective inhibitor of cyclooxygenase 2 on opioid consumption and outcomes after total knee arthroplasty (TKA). DESIGN, SETTING, AND PATIENTS: Randomized, placebo-controlled, double-blind trial conducted June 2001 through September 2002, enrolling 70 patients aged 40 to 77 years and undergoing TKA at a university hospital in the United States. INTERVENTIONS: Patients were randomly assigned to receive 50 mg of oral rofecoxib at 24 hours and at 1 to 2 hours before TKA, 50 mg daily for 5 days postoperatively, and 25 mg daily for another 8 days, or matching placebo at the same times. MAIN OUTCOME MEASURES: Postoperative outcomes including postsurgical analgesic consumption and pain scores achieved, nausea and vomiting, joint range of motion, sleep disturbance, patient satisfaction with analgesia, and hematologic and coagulation parameters. RESULTS: Total epidural analgesic consumption and in-hospital opioid consumption were less in the group receiving rofecoxib compared with the group receiving placebo (P<.05). Median pain score (visual analog scale [VAS], 0-10) achieved for the knee was lower in the rofecoxib group compared with the placebo group during hospital stay (2.2 [interquartile range [IQR], 1.4-3.2] vs 3.5 [IQR, 2.7-4.3], P<.001) and 1 week after discharge (2.6 [IQR, 1.4-3.5] vs 3.7 [IQR, 2.9-4.7], P =.03). There was less postoperative vomiting in the rofecoxib group (6%) compared with the placebo group (26%) (P =.047), as well as a decrease in sleep disturbance compared with the placebo group on the night of surgery (P =.006) and on the first (P =.047) and second (P<.001) days postoperatively. Knee flexion was increased in the rofecoxib group compared with the placebo group at discharge (active flexion: mean [SD], 84.2 degrees [11.1 degrees ] vs 73.2 degrees [13.6 degrees ], P =.03; passive flexion: 90.5 degrees [6.8 degrees ] vs 81.8 degrees [13.4 degrees ], P =.05) and at 1 month postoperatively (109.3 degrees [8.5 degrees ] vs 100.8 degrees [11.8 degrees ], P =.01), with shorter time in physical therapy to achieve effective joint range of motion. The rofecoxib group was more satisfied with analgesia and anesthesia at discharge compared with the placebo group (median satisfaction score, 4.3 [IQR, 3.0-4.7] vs 3.3 [IQR, 2.3-4.3], respectively; P =.03), and the differences persisted at 2-week and at 1-month follow-up. There was no intergroup difference in surgical blood loss (P>.05 for both intraoperative and postoperative blood loss). CONCLUSION: Perioperative use of an inhibitor of cyclooxygenase 2 is an effective component of multimodal analgesia that reduces opioid consumption, pain, vomiting, and sleep disturbance, with improved knee range of motion after TKA.

Rømsing et al 2004

A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for post-operative pain.

Rømsing J, Moiniche S.

Acta Anaesthesiol Scand 2004;48(5):525–546.

BACKGROUND: We have reviewed the analgesic efficacy of cyclooxygenase-2 (COX-2) inhibitors compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs), different COX-2 inhibitors, and placebo in post-operative pain. METHODS: Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia 0-24 h after surgery. RESULTS: Thirty-three studies were included in which four COX-2 inhibitors, rofecoxib 50 mg, celecoxib 200 and 400 mg, parecoxib 20, 40 and 80 mg, and valdecoxib 10, 20, 40, 80 mg were evaluated. Ten of these studies included 18 comparisons of rofecoxib, celecoxib, or parecoxib with NSAIDs. Rofecoxib 50 mg and parecoxib 40 mg provided analgesic efficacy comparable to that of the NSAIDs in the comparisons, and with a longer duration of action after dental surgery but possibly not after major procedures. Celecoxib 200 mg and parecoxib 20 mg provided less effective pain relief. Four studies included five comparisons of rofecoxib 50 mg with celecoxib 200 and 400 mg. Rofecoxib 50 mg provided superior analgesic effect compared with celecoxib 200 mg. Data on celecoxib 400 mg were too sparse for firm conclusions. Thirty-three studies included 62 comparisons of the four COX-2 inhibitors with placebo and the COX-2 inhibitors significantly decreased post-operative pain. CONCLUSION: Rofecoxib 50 mg and parecoxib 40 mg have an equipotent analgesic efficacy relative to traditional NSAIDs in post-operative pain after minor and major surgical procedures, and after dental surgery these COX-2 inhibitors have a longer duration of action. Besides, rofecoxib 50 mg provides superior analgesic effect compared with celecoxib 200 mg.

Greenberg et al 2000

A new cyclooxygenase-2 inhibitor, rofecoxib (VIOXX), did not alter the antiplatelet effects of low-dose aspirin in healthy volunteers.

The present study examined whether rofecoxib (VIOXX), a new specific inhibitor of cyclooxygenase-2 (COX-2), would interfere with the desired antiplatelet effects of aspirin. Thus, the effects of rofecoxib on inhibition of ex vivo serum-generated thromboxane B2 (TXB2) and platelet aggregation by low doses (81 mg) of aspirin were examined in healthy volunteers. This was a double-blind, randomized, placebo-controlled, parallel study of two treatment groups (n=12 per group) in which subjects received 50 mg of rofecoxib or placebo for 10 days in a blinded fashion. Subjects also received 81 mg aspirin once on each of days 4 through 10 in an open-label fashion. Blood for measurement of serum TXB2 production and platelet aggregation studies was collected on day 1 (prior to rofecoxib/placebo), on day 4 (prior to aspirin), and on day 10 (before and 4 hours following the seventh dose of aspirin). Platelet-derived serum TXB2 (COX-1 assay) was measured in blood clotted for 1 hour at 37oC. Platelet aggregation was independently induced employing 1 mM arachidonic acid and 1 µg/ml collagen as agonists. Rofecoxib administered alone had no significant effect on serum TXB2 production or platelet aggregation (day 4). TXB2 production was inhibited 98.4% by aspirin coadministered with either rofecoxib or placebo (day 10). Similarly, platelet aggregation induced by arachidonic acid was inhibited 93.7% and 93.5% by aspirin coadministered with either rofecoxib or placebo, respectively (day 10). The comparable values for inhibition of collagen-induced platelet aggregation were 86.8% and 90.8%, respectively. No important clinical or laboratory adverse experiences were observed. In conclusion, rofecoxib alone (50 mg QD for 4 days) did not inhibit serum TXB2 production or platelet aggregation. In addition, rofecoxib (50 mg QD for 10 days) did not alter the antiplatelet effects of low-dose aspirin (inhibition of platelet aggregation and TXB2 production). Rofecoxib was generally well tolerated when administered alone or in combination with low-dose aspirin.

Reuben et al 2002

Evaluation of the safety and efficacy of the perioperative administration of rofecoxib for total knee arthroplasty.

Reuben SS, Fingeroth R, Krushell R, Maciolek H.

J Arthroplasty 2002;17(1):26–31.

Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently are discontinued before elective total knee arthroplasty (TKA) because of the increased incidence of perioperative bleeding. Rofecoxib, a selective cyclooxygenase 2 inhibitor, does not interfere with the coagulation system and may be a safer NSAID for patients undergoing TKA. In this study, 100 patients undergoing elective TKA discontinued their use of NSAIDs 10 days before surgery and were assigned randomly to receive either placebo (n = 50) or rofecoxib (n = 50), 25 mg daily for 5 consecutive days starting 3 days before surgery. The administration of rofecoxib resulted in improved preoperative pain scores and no significant increase in the incidence of perioperative bleeding or international normalized ratio compared with placebo. Rofecoxib does not need to be discontinued before elective TKA.

BACKGROUND: Intolerance to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem in clinical practice. There is, therefore, a need for safer NSAIDs in patients with analgesic intolerance. OBJECTIVE: To assess the safety of nimesulide, meloxicam, and rofecoxib, selective COX-2 inhibitors, in a group of ASA/NSAIDs-intolerant patients. METHOD: Tolerances to nimesulide, meloxicam, and rofecoxib were assessed by single-blind placebo-controlled oral challenges. One hundred twenty-seven subjects with history of adverse reaction to ASA/NSAIDs received oral challenges with nimesulide, 61 subjects were challenged with meloxicam, 51 subjects were challenged with rofecoxib, and 37 subjects were challenged with all three drugs. Placebos were given to all patients on the first day of the study. On the second day, one-fourth and three-fourths of the therapeutic doses of the active drugs (nimesulide 100 mg, meloxicam 7.5 mg, or rofecoxib 25 mg) were given at 60-minute intervals. There was at least a 3-day interval between challenge tests. Erythema, pruritus accompanied by erythema, urticaria/angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea, or cough associated with a decrease of at least 20% in the forced expiratory volume (FEV1) and hypotension were considered as positive reactions. RESULTS: Positive reactions to the nimesulide, meloxicam, and rofecoxib challenges were observed in 18/127 (14.3%), 5/61 (8.1%), and 1/51 (2.0%) patients, respectively. In each group of nine patients, there were two patients with asthma and four who developed skin type reactions and asthmatic reactions, respectively, to the nimesulide challenge. Among five patients who reacted to the meloxicam challenge, asthmatic type reactions were detected in two asthmatics. Only one urticarial type reaction was observed with rofecoxib challenge in one patient who presented with anaphylaxis to ASA/NSAIDs. All patients with asthma tolerated rofecoxib without any adverse effects. None of the patients reacted to the placebo. Among 37 patients challenged with all three drugs, 11 reacted to nimesulide, and one patient reacted only to meloxicam. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs. CONCLUSION: This is the first placebo-controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAIDs-intolerant patients, rofecoxib seems to have the most favorable tolerability.

Nussmeier et al 2006

Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery.

Background: Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures. Methods: The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects. Results: Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01). Conclusions: Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.

Nussmeier et al 2005

Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.

Background Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain but may involve risk after coronary-artery bypass grafting (CABG). We conducted a randomized trial to assess the safety of these drugs after CABG. Methods In this randomized, double-blind study involving 10 days of treatment and 30 days of follow-up, 1671 patients were randomly assigned to receive intravenous parecoxib for at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo followed by oral valdecoxib; or placebo for 10 days. All patients had access to standard opioid medications. The primary end point was the frequency of predefined adverse events, including cardiovascular events, renal failure or dysfunction, gastroduodenal ulceration, and wound-healing complications. Results As compared with the group given placebo alone, both the group given parecoxib and valdecoxib and the group given placebo and valdecoxib had a higher proportion of patients with at least one confirmed adverse event (7.4% in each of these two groups vs. 4.0% in the placebo group; risk ratio for each comparison, 1.9; 95% confidence interval, 1.1 to 3.2; p = 0.02 for each comparison with the placebo group). In particular, cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo (2.0% vs. 0.5%; risk ratio, 3.7; 95% confidence interval, 1.0 to 13.5; p = 0.03). Conclusions The use of parecoxib and valdecoxib after CABG was associated with an increased incidence of cardiovascular events, arousing serious concern about the use of these drugs in such circumstances.

EMEA 2004a

Committee for Medicinal Products for Human Use, European Public Assessment Report (EPAR): Bextra.

EMEA.

Available at http://www.emea.eu.int/humandocs/Humans/EPAR/bextra/bextra.htm

Blomme et al 2003

Selective cyclooxygenase-2 inhibition does not affect the healing of cutaneous full-thickness incisional wounds in SKH-1 mice.

BACKGROUND: The inducible cyclooxygenase-2 (COX-2) enzyme is upregulated in inflammatory diseases, as well as in epithelial cancers, and has an established role in angiogenesis and tissue repair. OBJECTIVE: Because of these physiological effects and the widespread use of the selective COX-2 inhibitor, celecoxib, we wanted to determine if inhibition of COX-2 would affect incisional skin wound healing. METHODS: Using a cutaneous full-thickness, sutured, incisional wound model in hairless SKH-1 mice, we evaluated the role of COX-2 in the wound healing process by comparing the effects of a nonselective COX inhibitor, diclofenac, with a selective COX-2 inhibitor, SC-791. Healing was monitored for up to 28 days postincision histologically and for recovery of wound strength. RESULTS: COX-2 expression was observed over the first week of healing, peaking at day 3 and was not affected by treatment with the selective COX-2 or nonselective COX inhibitors. Infiltrating macrophages, as well as keratinocytes and dermal fibroblasts at the wound site, expressed COX-2. Neither selective COX-2, nor nonselective COX inhibition had a significant effect on the macroscopic or microscopic morphology of the wounds, whereas dexamethasone treatment resulted in epidermal and granulation tissue atrophy. In addition, neither selective COX-2, nor nonselective COX inhibition altered keratinocyte proliferation and differentiation, dermal angiogenesis or the recovery of wound tensile strength, whereas dexamethasone reduced the tensile strength of the wounds by 30-38% throughout the healing period. CONCLUSIONS: These data indicate that selective COX-2 inhibition does not affect the healing of surgical skin wounds.

Ozyalcin et al 2004

Effect of pre-emptive ketamine on sensory changes and postoperative pain after thoracotomy: comparison of epidural and intramuscular routes.

BACKGROUND: In this study we have evaluated the efficacy of ketamine via i.m. and epidural routes for the control of post-thoracotomy pain. METHODS: The study was randomized, double blinded and placebo controlled. With the approval of the Faculty Ethics Committee, 60 patients undergoing elective thoracotomy were randomized into three equal groups. Group IM had i.m. ketamine 1 mg kg(-1) in 2 ml plus epidural normal saline; Group EPI had epidural ketamine 1 mg kg(-1) in 10 ml plus i.m. normal saline; Group C had epidural normal saline 10 ml plus i.m. normal saline 10 ml. Anaesthesia was standardized. Postoperative analgesia was maintained with epidural patient-controlled analgesia using bupivacaine and morphine. Visual analogue scale values and analgesic consumption were evaluated at 2, 4, 6, 8, 10, 12, 24 and 48 h after surgery. The areas of allodynia, pin-prick hyperalgesia and pressure hyperalgesia were measured at 48 h, and days 15 and 30 in all groups. RESULTS: Intraoperative fentanyl requirement was significantly lower in Group EPI than Group C. The morphine and bupivacaine requirements were significantly lower in Group EPI than the other two groups in the postoperative period. There was reduced pin-prick hyperalgesia and touch allodynia in the EPI group. There were no side-effects attributable to ketamine. CONCLUSION: The results of the present study demonstrate that pre-emptive epidural ketamine is effective in reducing intra- and postoperative analgesic requirements, hyperalgesia and touch allodynia.

BACKGROUND: Post-operative pain management is usually limited by adverse effects such as nausea and vomiting. Adjuvant treatment with an inexpensive opioid-sparing drug such as ketamine may be of value in giving better analgesia with fewer adverse effects. The objective of this systematic review was to evaluate the effectiveness and tolerability of ketamine administered peri-operatively in the treatment of acute post-operative pain in adults. METHODS: Studies were identified from MEDLINE (1966-2004), EMBASE (1980-2004), the Cochrane Library (2004) and by hand searching reference lists from review articles and trials. The manufacturer of ketamine (Pfizer AS, Lysaker, Norway) provided search results from their in-house database, PARDLARS. Randomized and controlled trials (RCTs) of adult patients undergoing surgery, being treated with peri-operative ketamine, placebo or an active control were considered for inclusion. RESULTS: Eighteen trials were excluded. Thirty-seven trials were included. Twenty-seven out of 37 trials found that peri-operative ketamine reduced rescue analgesic requirements or pain intensity, or both. Quantitative analysis showed that treatment with ketamine reduced 24-h patient-controlled analgesia (PCA) morphine consumption and post-operative nausea and vomiting (PONV). Adverse effects were mild or absent. CONCLUSION: In the first 24 h after surgery, ketamine reduces morphine requirements. Ketamine also reduces PONV. Adverse effects are mild or absent. These data should be interpreted with caution as the retrieved studies were heterogenous and the result of the meta-analysis can not be translated into any specific administration regimen with ketamine.

Dahl et al 2004

'Protective premedication': an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain.

Dahl JB, Mathiesen O, Moiniche S.

Acta Anaesthesiol Scand 2004;48:1130–1136.

Substantial progress has been made during the last decades in our understanding of acute pain mechanisms, and this knowledge has encouraged the search for novel treatments. Of particular interest has been the observation that tissue injury initiates a number of modulations of both the peripheral and the central pain pathways, which convert the system from a 'physiological' to a 'pathological' mode of processing afferent information. Gabapentin, which binds to the alpha(2)delta subunit of the voltage-dependent calcium channel, is active in animal models of 'pathological' but not in models of 'physiological' pain. Consequently, attention has so far been focused on neuropathic pain as a target for the clinical use of gabapentin and analogues. Recently, several reports have indicated that gabapentin may have a place in the treatment of post-operative pain. This article presents a brief summary of the potential mechanisms of post-operative pain, and a systematic review of the available data of gabapentin and pregabalin for post-operative analgesia. It is concluded that the results with gabapentin and pregabalin in post-operative pain treatment published so far are promising. It is suggested that future studies should explore the effects of 'protective premedication' with combinations of various antihyperanalgesic and analgesic drugs for post-operative analgesia.

Acta Anaesthesiol Scand 1999;43(7):770–4.Synergism between gabapentin and morphine in treating incisional pain has been demonstrated in animal experiments and clinical studies. The efficacy of gabapentin for treatment of perioperative pain remains controversial. This study was designed to detect the influence of gabapentin premedication on morphine consumption in the immediate postoperative period in patients undergoing lumbar laminectomy and discectomy. Either gabapentin 800 mg (in two equally divided doses) or placebo was given preoperatively to 60 adult patients undergoing elective lumbar laminectomy or discectomy in a double-blinded, placebo-controlled, randomized study. Standard general anesthesia was given to all the patients. Morphine was administered via patient-controlled analgesia pump in the immediate postoperative period for first 8 hours. Pain at rest and on movement was assessed using a Verbal Rating Scale (VRS) every 2 hours for the first 8 postoperative hours. There were no differences in demographics or surgical duration between the two groups. The amount of fentanyl administered in the intraoperative period was similar between the two groups. In the postoperative period, the VRS score for pain at 0, 2, 4, 6, and 8 hours was not significantly different between the two groups. Highest median VRS score was recorded at 0 hours postoperatively in both groups (VRS: rest = 6, movement = 8 in placebo group; rest = 6, movement = 8 in gabapentin group). Total morphine consumption and side effects were similar in the two groups. Gabapentin does not decrease the morphine requirement or morphine side effects in the immediate postoperative period following lumbar laminectomy and discectomy.

OBJECTIVE. Thoracotomy results in severe pain and deleterious changes in pulmonary physiology. The literature suggests that these alterations in pulmonary mechanics are inevitable and can only be minimised but not prevented by effective analgesia. We have re-evaluated this concept and assessed the efficacy of pre-emptive analgesia [preincisional afferent block, premedication with opiate and/or non-steroidal anti-inflammatory drug (NSAID)] in conjunction with postoperative extrapleural continuous intercostal nerve block on postoperative pain and pulmonary function. MATERIALS AND METHODS. A prospective randomized study was conducted on 56 patients undergoing elective thoracotomy. Subjective pain relief was assessed on a linear visual analogue scale. Pulmonary function was measured on the day before operation and 12 hourly for 48 hours after operation. There were seven patients in each of the eight groups. RESULTS. The balanced analgesia group comprising preincisional block and premedication with opiate and NSAID (Group 1) had significantly better analgesia, needed less postoperative supplementary analgesics and maintained their preoperative pulmonary function postoperatively irrespective of the nature of the operation. The ranking of importance of the three components of the pre-emptive analgesia as assessed in this study are preincisional block, opiate premedication and premedication with NSAID's. No significant change in plasma levels of cortisol or glucose occurred in Group 1 patients from prior to induction of anaesthesia to 24 hours postoperatively, suggesting effective somatic and sympathetic afferent blockade had been achieved in these patients. There were no complications related to the infusion or the use of NSAID's. CONCLUSIONS. We conclude that a balanced analgesic regime comprising preoperative pain prophylaxis and postoperative maintenance analgesia by NSAID and continuous extrapleural intercostal nerve block will minimise and even reverse the expected decline in lung function after thoracotomy. The postoperative decline in lung function is not obligatory but primarily due to incisional pain and thus is preventable by effective analgesia. An ideal balanced pre-emptive analgesic regime should include preincisional local anaesthetic afferent block and premedication with opiates and a NSAID.

Wheeler et al 2002

Aguilar et al 1996

Absence of an early pre-emptive effect after thoracic extradural bupivacaine in thoracic surgery.

Aguilar JL, Rincon R, Domingo V, Espachs P, Preciado MJ, Vidal F.

British Journal of Anaesthesia 1996;76(1):72–76.

We have determined if thoracic extradural block before surgical incision for thoracotomy produces pre-emptive analgesia. Using a double-blind, placebo-controlled, crossover design, 45 patients (ASA II-III) undergoing posterolateral thoracotomy for lung resection were randomized to one of three groups: group 1 received 0.5% bupivacaine and adrenaline 1/200,000 (B+E) 8 ml through a thoracic extradural catheter (tip T3-T5) 30 min before skin incision and saline 8 ml 15 min after skin incision; group 2 received saline 8 ml extradurally before incision and B+E 8 ml after incision; group 3 received saline 8 ml extradurally before and after incision. General anaesthesia was induced and maintained with propofol, alfentanil and atracurium. The alfentanil infusion was stopped before chest closure and fentanyl 50 micrograms in saline 10 ml was given extradurally. Patient-controlled extradural analgesia (PCEA) was commenced with 0.125% bupivacaine, adrenaline 1/400,000 and fentanyl 6 micrograms ml-1 (continuous rate of 2 ml h-1 and supplementary doses of 0.5 ml per 6 min). Visual analogue scale (VAS) scores (recorded at rest, on mobilization and after cough), verbal rating scale (VRS) (recorded at rest), number of successful PCEA demands and complications were measured during the first 48 h after operation. There was no significant difference between groups, either in PCEA requirements (P > 0.21) or in VAS scores (either at rest, during mobilization of the ipsilateral arm of surgery or after cough). No significant differences between groups were found in the VRS. Thoracic extradural block with bupivacaine did not produce an early preemptive effect after thoracotomy.

Neustein et al 2002

The purpose of this study was to determine if preemptive epidural analgesia performed before thoracotomy incision and during the operation reduces postoperative pain. Patients in the treatment group received 8 mL of 0.25% bupivacaine and 2 mL of fentanyl (50 microg/mL) via the epidural route prior to skin incision, followed by an infusion of bupivacaine 0.1% and fentanyl 10 microg/mL at 6 mL/hr. The control group received saline in the epidural. All patients in both groups were dosed with 8 mL of 0.25% bupivacaine and 2 mL of fentanyl 50 microg/mL via the epidural route at the time of the chest closure. The patients in the treatment group required less isoflurane intraoperatively and had lower maximum pain scores in the first 6 hours postoperatively. No significant differences were noted after the first 6 hours.

Rosseel et al 1988

Epidural sufentanil for intra- and postoperative analgesia in thoracic surgery: a comparative study with intravenous sufentanil.

Rosseel PM, van den Broek WG, Boer EC, Prakash O.

Acta Anaesthesiologica Scandinavica 1988;32(3):193–8.

A comparative study was undertaken to evaluate the effectiveness of epidural sufentanil in providing intra- and postoperative analgesia during thoracic surgery. Sufentanil was chosen on the basis of its high lipid solubility and its potent opiate receptor binding. Epidural sufentanil was compared with intravenous sufentanil as the major intraoperative analgetic agent in an anesthesia regimen with midazolam and nitrous oxide. Epidural sufentanil significantly decreased the need for supplementary intravenous analgesia. In the epidural sufentanil group the immediate postoperative analgesia was found to be better, with a longer duration of action, compared with the intravenous sufentanil group. Postoperatively epidural sufentanil was compared with epidural morphine. Sufentanil provided good analgesia with a very fast onset and a mean duration of almost 7 h. Severe respiratory depression was observed in one patient within 1 h of extubation, probably due to the combined effects of the narcotic administration and residual midazolam. It is concluded that 50 micrograms of sufentanil administered in the thoracic epidural space provides valuable intraoperative analgesia which can easily be extended into the postoperative period, although all necessary precautions for epidural opiate administration should be taken.

Senturk et al 2002

The effects of three different analgesia techniques on long-term postthoracotomy pain.

In this clinical, randomized, prospective study, we compared the effects of three different analgesia techniques (thoracic epidural analgesia [TEA] with and without preoperative initiation and IV patient-controlled analgesia [IV-PCA]) on postthoracotomy pain in 69 patients. In two groups, a thoracic epidural catheter was inserted preoperatively. Group Pre-TEA had bupivacaine and morphine solution preoperatively and intraoperatively. Postoperative analgesia was maintained with epidural PCA with a similar solution. Group Post-TEA, with no intraoperative medication, had the same postoperative analgesia as Group Pre-TEA plus the bolus dose. Group IV-PCA received only IV-PCA with morphine for postoperative analgesia. Pain was evaluated every 4 h during the first 48 h at rest, cough, and movement. Pre-TEA was associated with decreased pain compared with the other groups. Six months later, the patients were asked about their pain. The incidence and the intensity of pain were most frequent in Group IV-PCA (78%) and were the least in Group Pre-TEA (45%) (Group Pre-TEA versus Group IV-PCA, P = 0.0233; Group Pre-TEA versus Group IV-PCA, P = 0.014). Patients having pain on the second postoperative day had 83% chronic pain. TEA with preoperative initiation is a preferable method in preventing acute and long-term thoracotomy pain. IMPLICATIONS: Preoperatively initiated thoracic epidural analgesia has the most satisfying results in controlling postthoracotomy pain in the acute and long-term period, and it is associated with a decreased incidence (and intensity) of chronic pain compared with postoperative (epidural or IV) analgesia. Chronic pain has an incidence of 62%.

Ochroch et al 2002

Long-term pain and activity during recovery from major thoracotomy using thoracic epidural analgesia.

BACKGROUND: Pain following thoracotomy can persist for years with an undetermined impact on quality of life. Factors hypothesized to modulate this painful experience include analgesic regimen, gender, and type of incision. METHODS: A total of 157 generally healthy patients of both genders scheduled for segmentectomy, lobectomy, or bilobectomy through a posterolateral or muscle-sparing incision were randomly assigned to receive thoracic epidural analgesia initiated prior to incision or at the time of rib approximation. Pain and activity scores were obtained 4, 8, 12, 24, 36, and 48 weeks after surgery. RESULTS: Overall, there were no differences in pain scores between the control and intervention groups during hospitalization (P >or= 0.165) or after discharge (P>or= 0.098). The number of patients reporting pain 1 yr following surgery (18 of 85; 21.2%) was not significantly different (P = 0.122) from the number reporting preoperative pain (15 of 120; 12.5%). During hospitalization, women reported greater pain than men (worst pain, P= 0.007; average pain, P= 0.016). Women experienced fewer supraventricular tachydysrhythmias (P = 0.013) and were thus discharged earlier (P = 0.002). After discharge women continued to report greater discomfort than men (P <or= 0.016), but did not differ from men in their level of physical activity (P = 0.241). CONCLUSIONS: Initiation of thoracic epidural analgesia prior to incision or the use of a muscle-sparing incision did not significantly impact pain or physical activity. Although women reported significantly greater pain during hospitalization and after discharge, they experienced fewer complications, were more likely to be discharged from the hospital sooner, and were just as active after discharge as men.

We performed meta-analyses of randomized, control trials to assess the effects of seven analgesic therapies on postoperative pulmonary function after a variety of procedures: epidural opioid, epidural local anesthetic, epidural opioid with local anesthetic, thoracic versus lumbar epidural opioid, intercostal nerve block, wound infiltration with local anesthetic, and intrapleural local anesthetic. Measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), vital capacity (VC), peak expiratory flow rate (PEFR), PaO2, and incidence of atelectasis, pulmonary infection, and pulmonary complications overall were analyzed. Compared with systemic opioids, epidural opioids decreased the incidence of atelectasis (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.33–0.85) and had a weak tendency to reduce the incidence of pulmonary infections (RR 0.53, 95% CI 0.18–1.53) and pulmonary complications overall (RR 0.51, 95% CI 0.20–1.33). Epidural local anesthetics increased PaO2 (difference 4.56 mm Hg, 95% CI 0.058–9.075) and decreased the incidence of pulmonary infections (RR 0.36, 95% CI 0.21–0.65) and pulmonary complications overall (RR 0.58, 95% CI 0.42–0.80) compared with systemic opioids. Intercostal nerve blockade tends to improve pulmonary outcome measures (incidence of atelectasis: RR 0.65, 95% CI 0.27–1.57, incidence of pulmonary complications overall: RR 0.47, 95% CI 0.18–1.22), but these differences did not achieve statistical significance. There were no clinically or statistically significant differences in the surrogate measures of pulmonary function (FEV1, FVC, and PEFR). These analyses support the utility of epidural analgesia for reducing postoperative pulmonary morbidity but do not support the use of surrogate measures of pulmonary outcome as predictors or determinants of pulmonary morbidity in postoperative patients. IMPLICATIONS: When individual trials are unable to produce significant results, it is often because of insufficient patient numbers. It may be impossible for a single institution to study enough patients. Meta-analysis is a useful tool for combining the data from multiple trials to increase the patient numbers. These meta-analyses confirm that postoperative epidural pain control can significantly decrease the incidence of pulmonary morbidity.

Chaney 1995

Side effects of intrathecal and epidural opioids.

Chaney MA.

Can J Anaesth. 1995;42:891–903.

The purpose of this article is to review the literature on the side effects of intrathecal and epidural opioids. English-language articles were identified through a MEDLINE search and through review of the bibliographies of identified articles. With the increasing utilization of intrathecal and epidural opioids in humans during the 1980s, a wide variety of clinically relevant side effects have been reported. The four classic side effects are pruritus, nausea and vomiting, urinary retention, and respiratory depression. Numerous other side effects have also been described. Most side effects are dose-dependent and may be more common if the opioid is administered intrathecally. Side effects are less common in patients chronically exposed to either intrathecal, epidural, or systemic opioids. Some side effects are mediated via interaction with specific opioid receptors while others are not. It is concluded that the introduction of intrathecal and epidural opioids marks one of the most important breakthroughs in pain management in the last two decades. However, a wide variety of clinically relevant non-nociceptive side effects may occur. All physicians utilizing intrathecal and epidural opioids must be aware of these side effects, for while most are minor, others are potentially lethal.

Recent evidence suggests that surgical incision and other noxious perioperative events may induce prolonged changes in central neural function that later contribute to postoperative pain. The present study tested the hypothesis that patients receiving epidural fentanyl before incision would have less pain and need fewer analgesics post-operatively than patients receiving the same dose of epidural fentanyl after incision. Thirty patients (ASA physical status 2) scheduled for elective thoracic surgery through a posterolateral thoracotomy incision were randomized to one of two groups of equal size and prospectively studied in a double-blind manner. Epidural catheters were placed via the L2-L3 or L3-L4 interspaces preoperatively, and the position was confirmed with lidocaine. Group 1 received epidural fentanyl (4 micrograms/kg, in 20 ml normal saline) before surgical incision, followed by epidural normal saline (20 ml) infused 15 min after incision. Group 2 received epidural normal saline (20 ml) before surgical incision, followed by epidural fentanyl (4 micrograms/kg, in 20 ml normal saline) infused 15 min after incision. No additional analgesics were used before or during the operation. Anesthesia was induced with thiopental (3-5 mg/kg) and maintained with N2O/O2 and isoflurane. Paralysis was achieved with pancuronium (0.1 mg/kg). Postoperative analgesia consisted of patient-controlled intravenous morphine. Visual analogue scale pain scores were significantly less in group 1 (2.6 +/- 0.44) than in group 2 (4.7 +/- 0.58) 6 h after surgery (P less than 0.05), by which time plasma fentanyl concentrations had decreased to subtherapeutic levels (less than 0.15 ng/ml) in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to evaluate the potential analgesic effect of epidural methylprednisolone (MP) after posterolateral thoracotomy (PLT). Adult male patients undergoing PLT for lung surgery were included in a prospective, randomized, double blind study. Peroperative analgesia (bupivacaine plus sufentanil) was given by a thoracic epidural catheter associated with general anaesthesia. After surgery, patients received either MP 1 mg kg(-1) followed by a continuous epidural infusion of MP 1.5 mg kg(-1) during 48 h (MP group) or 0.9% saline as a bolus injection and continuous epidural infusion (P group). Additional morphine analgesia was administered by i.v. patient-controlled analgesia. Pain was assessed at rest and with mobilization every 4 h after operation during 48 h with a visual analogue scale (VAS). The primary end-point was the total morphine requirements during the 48 first postoperative hour. Twenty-four patients were allocated to MP (n=12) and P (n=12) groups. Characteristics of the two groups were similar. There were no differences between groups for morphine requirements (median and interquartile range) during the 48 h: 59 mg (40-78) in MP group vs 65 mg (59-93) in P group. There were no differences between groups for morphine requirements every 4 h during the 48 h and VAS for pain at rest and evoked pain. No side effects were reported. It was concluded in this small study that these results did not support the use of epidural steroids for postoperative analgesia after PLT.

Niemi et al 1998

Adrenaline markedly improves thoracic epidural analgesia produced by a low-dose infusion of bupivacaine, fentanyl and adrenaline after major surgery.

Niemi G, Breivik H.

Acta Anaesthesiol Scand 1998;42(8):897–909.

BACKGROUND: Basic pharmacological research indicates that there are synergistic antinociceptive effects at the spinal cord level between adrenaline, fentanyl and bupivacaine. Our clinical experience with such a mixture in a thoracic epidural infusion after major surgery confirms this. The objectives of the present study were to evaluate the effects on postoperative pain intensity, pain relief and side effects when removing adrenaline from this triple epidural mixture. METHODS: A prospective, randomised, double-blind, cross-over study was carried out in 24 patients after major thoracic or abdominal surgery. Patients with only mild pain when coughing during a titrated thoracic epidural infusion of about 10 ml.h-1 of bupivacaine 1 mg.ml-1, fentanyl 2 micrograms.ml-1, and adrenaline 2 micrograms.ml-1 were included. On the 1st and 2nd postoperative days each patient was given a double-blind epidural infusion, at the same rate, with or without adrenaline. The effect was observed for 4 h or until pain when coughing became unacceptable in spite of a rescue analgesic procedure. Rescue analgesia consisted of up to two epidural bolus injections per hour and i.v. morphine if necessary. All patients received rectal paracetamol 1 g, every 8 h. Fentanyl serum concentrations were measured with a radioimmunoassay technique at the start and end of each study period. Main outcome measures were extent of sensory blockade and pain intensity at rest and when coughing, evaluated by a visual analogue scale, a verbal categorical rating scale, the Prince Henry Hospital pain score, and an overall quality of pain relief score. RESULTS: The number of hypaesthetic dermatomal segments decreased (P < 0.001) and pain intensity at rest and when coughing increased (P < 0.001) when adrenaline was omitted from the triple epidural mixture. This change started within the first hour after removing adrenaline. After 3 h pain intensity when coughing had increased to unacceptable levels in spite of rescue analgesia (epidural bolus injections and i.v. morphine). Within 15-20 min after restarting the triple epidural mixture with adrenaline, pain intensity was again reduced to mild pain when coughing. Serum concentration of fentanyl doubled from 0.22 to 0.45 ng.ml-1 (P < 0.01), and there was more sedation during the period without adrenaline. CONCLUSIONS: Adrenaline increases sensory block and improves the pain-relieving effect of a mixture of bupivacaine and fentanyl infused epidurally at a thoracic level after major thoracic or abdominal surgery. Serum fentanyl concentrations doubled and sedation increased when adrenaline was removed from the epidural infusion, indicating more rapid vascular absorption and systemic effects of fentanyl.

Niemi et al 2003

The minimally effective concentration of adrenaline in a low-concentration thoracic epidural analgesic infusion of bupivacaine, fentanyl and adrenaline after major surgery.

Niemi G, Breivik H.

Acta Anaesthesiol Scand 2003;47(4):439–50.

BACKGROUND: We have documented that adrenaline 2.0 micro g.ml-1 markedly improves relief of dynamic pain when added to a thoracic epidural analgesic infusion of bupivacaine 1 mg.ml-1 and fentanyl 2 micro g.ml-1. Concern about possible adverse effects on spinal cord blood flow, expressed by others, prompted us to find the lowest concentration of adrenaline needed to produce effective and reliable pain relief after major surgery. METHODS: A prospective, randomized, double-blind, parallel group study was carried out in 36 patients after major thoracic or upper abdominal surgery. Patients with only mild pain when coughing during titrated thoracic epidural infusion of approximately 9 ml per hour of bupivacaine 1 mg.ml-1, fentanyl 2 micro g.ml-1, and adrenaline 2.0 micro g.ml-1 were included. The study was conducted as a dose-finding study comparing three different adrenaline concentrations in the epidural mixture (0.5, 1.0, and 1.5 micro g.ml-1) with each other and with adrenaline 2.0 micro g.ml-1 in our standard epidural mixture. On the 1st postoperative day, the patients were randomly allocated into three equal groups of 12 patients each, and given a double-blind epidural infusion at the same rate, but with different adrenaline concentrations (0.5, 1.0, or 1.5 micro g.ml-1). The effects were observed for 4 h or until pain when coughing became unacceptable in spite of rescue analgesia. Rescue analgesia consisted of up to two patient-controlled epidural bolus injections per hour (4 ml) and subsequent i.v. morphine, if necessary. All patients received rectal paracetamol 1 g, every 6th hour. Main outcome measures were pain intensity at rest and when coughing, evaluated by a visual analogue scale and an overall quality of pain relief score. The extent of sensory blockade was evaluated by determining dermatomal hypaesthesia to cold. RESULTS: Pain intensity when coughing increased (P < 0.001) and the number of hypaesthetic dermatomal segments decreased (P < 0.002) when the concentration of adrenaline was reduced below 1.5 micro g.ml-1 in the triple epidural mixture. This change started within two hours after reducing the concentration of adrenaline below 1.5 micro g.ml-1. The differences in pain intensities at rest were less pronounced. After 4 h with adrenaline 0.5 or 1.0 micro g.ml-1 pain intensity when coughing was unacceptable in spite of rescue analgesia. After restarting the standard epidural mixture with adrenaline 2.0 micro g.ml-1, pain intensity was again reduced to mild pain when coughing and the sensory blockade was restored. Occurrence of pruritus increased with a decreasing adrenaline concentration. CONCLUSIONS: Adrenaline in a dose-related manner improves the pain-relieving effect and sensory blockade and decreases the occurrence of pruritus of a low-concentration thoracic epidural analgesic infusion of bupivacaine 1 mg. ml-1 and fentanyl 2 micro g.ml-1 after major thoracic or upper abdominal surgery. The minimally effective concentration of adrenaline, when added to bupivacaine 1 mg.ml-1 and fentanyl 2 micro g.ml-1, to maintain relief of dynamic pain is approximately 1.5 micro g.ml-1. The data clearly document that dynamic, cough-provoked pain is a more sensitive outcome measure for postoperative pain relief than pain at rest.

We compared the analgesic effect of lumbar intrathecal (IT) 0.5 mg morphine (Group M, n = 10), 50 microg sufentanil (Group S, n = 10), and their combination (Group S-M, n = 10) given before general anesthesia and patient-controlled analgesia with IV morphine (Group C, n = 19) in a randomized, double-blinded study performed in patients undergoing thoracotomy. Pain visual analog scale (VAS) and morphine consumption were assessed for 24 h. In Group S-M the number of patients initially titrated with IV morphine was less than in group C (30 vs 84%, P < 0.05). Morphine requirement was higher in Group C (71 +/- 30 mg) than in Groups S (46 +/- 34 mg, P < 0.05), M (38 +/- 31 mg, P < 0.05) and S-M (23 +/- 16 mg, P < 0.01). VAS scores were significantly decreased during the first 0-11 postoperative h at rest and during the first 0-8 postoperative h on coughing in Groups M and S-M rather than in Group C. The incidence of side effects was infrequent except for urinary retention. Preoperative IT morphine or combined sufentanil and morphine could be given as a booster to achieve rapidly effective analgesia in the immediate postoperative period. Implications: As compared with IV patient-controlled analgesia, intrathecal morphine or combined sufentanil and morphine provided superior postoperative pain relief both at rest (11 h) and on coughing (8 h) than did IV patient-controlled analgesia morphine alone. IV morphine requirement was decreased during the first postoperative day after posterolateral thoracotomy.

Cohen et al 1993

The ability of intrathecal morphine to reduce the anesthetic requirements during thoracotomy was investigated. Twenty-four patients scheduled for thoracic surgery were studied. Anesthesia was induced with thiamylal sodium, 4 mg/kg, fentanyl, 100 micrograms, and 100 mg of succinylcholine. Prior to skin incision, 12 patients received intrathecal injection of 12 micrograms/kg of preservative-free morphine sulfate (ITM), while the remaining 12 patients served as controls. The ITM was given undiluted at the L3-4 or L4-5 level. Anesthesia was maintained solely with enflurane, titrated to keep mean arterial pressure within 15% of the preoperative values. Vecuronium was given as required for relaxation. No additional narcotics were administered. Throughout the procedure, end-tidal (ET) enflurane concentration was recorded at 15-minute intervals from the mass spectrometer (Perkin Elmer). The intraoperative mean ET concentration of enflurane was significantly reduced in the ITM group beginning 1 hour after the injection (1.19 +/- .45% in the control group versus 0.73 +/- 0.08% in the ITM group). The enflurane requirements, expressed as percent end-tidal enflurane/hour, were significantly less in the ITM group for the duration of the procedure (0.8 +/- .17 v 1.08 +/- .22, respectively). In conclusion, when administered prior to skin incision for post-thoracotomy pain control, intrathecal morphine reduces intraoperative enflurane requirements.

Bowler et al 2002

A combination of intrathecal morphine and remifentanil anesthesia for fast-track cardiac anesthesia and surgery.

Bowler I, Djaiani G, Abel R, Pugh S, Dunne J, Hall J.

Journal of Cardiothoracic & Vascular Anesthesia 2002;16(6):709–14.

OBJECTIVE: To determine if the combined remifentanil and intrathecal morphine (RITM) anesthetic technique facilitates early extubation in patients undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: Referral center for cardiothoracic surgery at a university hospital. PARTICIPANTS: Patients (n = 24) undergoing first-time elective CABG surgery. INTERVENTIONS: Two groups represented RITM (n = 12) and fentanyl-based (controls, n = 12) anesthesia. Premedication was standardized to temazepam, 0.4 mg/kg, and anesthesia was induced with etomidate, 0.3 mg/kg, in both groups. The RITM group received remifentanil, 1 microg/kg bolus followed by 0.25 to 1 microg/kg/min infusion, and intrathecal morphine, 2 mg. The control group received fentanyl, 12 microg/kg in 3 divided doses. Anesthesia was maintained with isoflurane and pancuronium in both groups. After completion of surgery, the remifentanil infusion was stopped. Complete reversal of muscle relaxation was ensured with a nerve stimulator, and a propofol infusion, 0.5 to 3 mg/kg/h, was started in both groups. All patients were transferred to the intensive care unit (ICU) to receive standardized postoperative care. Intensivists and ICU nurses were blinded to the group assignment. Propofol infusion was stopped, and the tracheal extubation was accomplished when extubation criteria were fulfilled. MEASUREMENTS AND MAIN RESULTS: Both groups were similar with respect to demographic data and surgical characteristics. Extubation times were 156 +/- 82 minutes and 258 +/- 91 minutes in the RITM and control groups (p = 0.012). Patients in the RITM group exhibited lower visual analog scale pain scores during the first 2 hours after extubation (p < 0.04). Morphine requirements during the 24 hours after extubation were 2.5 +/- 3 mg in the RITM group and 16 +/- 11 mg in the control group (p = 0.0018). Sedation scores were lower in the RITM group during the first 3 hours after extubation (p < 0.03). Pulmonary function tests as assessed by spirometry were better in the RITM group at 6 and 12 hours after extubation (p < 0.04). There were no significant differences in PaO(2) and PaCO(2) after extubation between the 2 groups. None of the patients had episodes of apnea during the immediate 24-hour postextubation period. Two patients from the RITM group required reintubation on the second and sixth postoperative days. There were no differences in ICU and hospital length of stay between the 2 groups. CONCLUSION: Implementation of the RITM technique provided earlier tracheal extubation, decreased level of sedation, excellent analgesia, and improved spirometry in the early postoperative period. The impact of RITM on ICU and hospital length of stay and potential cost benefits require further evaluation. Copyright 2002, Elsevier Science (USA). All rights reserved.

Mason et al 2001

Intrathecal sufentanil and morphine for post-thoracotomy pain relief.

Mason N, Gondret R, Junca A, Bonnet F.

British Journal of Anaesthesia 2001;86(2):236–40.

In this double-blind randomized study we compared a group of 15 patients undergoing thoracotomy who received a spinal injection of sufentanil 20 microg combined with morphine (200 microg) after induction of general anaesthesia with a control group of the same size. Post-operative pain was rated on a visual analogue scale (VAS) and a verbal rating scale at rest and with a VAS on coughing. In the recovery room, patients received titrated i.v. morphine until the VAS score was <30, and were followed by patient-controlled analgesia (PCA) for 72 h. The intrathecal sufentanil and morphine group had a lower intra-operative requirement for i.v. sufentanil and needed less i.v. morphine for titration in the recovery room. I.v. PCA morphine consumption and pain scores were lower in the active group than in the control group during the first 24 h. There were no differences after this time. Spirometric data (peak expiratory flow, forced vital capacity and forced expiratory volume in 1 s) were similar in the two groups. We conclude that the combination of intrathecal sufentanil and morphine produces analgesia of rapid onset and with a duration of 24 h.

Liu et al 2004

BACKGROUND: Perioperative central neuraxial analgesia may improve outcome after coronary artery bypass surgery due to attenuation of stress response and superior analgesia. METHODS: MEDLINE and other databases were searched for randomized controlled trials in patients undergoing coronary artery bypass surgery with cardiopulmonary bypass who were randomized to either general anesthesia (GA) versus general anesthesia-thoracic epidural analgesia (TEA) or general anesthesia-intrathecal analgesia (IT). RESULTS: Fifteen trials enrolling 1178 patients were included for TEA analysis. TEA did not affect incidences of mortality (0.7% TEA vs. 0.3% GA) or myocardial infarction (2.3% TEA vs. 3.4% GA). TEA significantly reduced the risk of dysrhythmias with an odds ratio of 0.52, pulmonary complications with an odds ratio of 0.41, and time to tracheal extubation by 4.5 h and reduced analog pain scores at rest by 7.8 mm and with activity by 11.6 mm. Seventeen trials enrolling 668 patients were included for IT analysis. IT had no significant effect on incidences of mortality (0.3% IT vs. 0.6% GA), myocardial infarction (3.9% IT vs. 5.7% GA), dysrhythmias (24.8% vs. 29.1%), nausea/vomiting (31.3% vs. 28.5%), or time to tracheal extubation (10.4 h IT vs. 10.9 h GA). IT modestly decreased systemic morphine use by 11 mg and decreased pain scores by 16 mm. IT significantly increased the incidence of pruritus (10% vs. 2.5%). CONCLUSIONS: There were no differences in the rates of mortality or myocardial infarction after coronary artery bypass grafting with central neuraxial analgesia. There were associated improvements in faster time until tracheal extubation, decreased pulmonary complications and cardiac dysrhythmias, and reduced pain scores.

Mozell et al 1991

A randomised, double blind trial was carried out in 16 patients undergoing pleurectomy to assess the effect of continuous extrapleural intercostal block on postoperative pain and pulmonary function. Subjective pain relief was assessed on a linear visual analogue scale. Pulmonary function was measured on the day before operation and daily for five days after surgery. Eight patients received bupivacaine and eight placebo (saline). The mean pain scores at 4, 8, 16, and 24 hours were 13.3, 8.5, 6.1, and 10 mm respectively in the bupivacaine group compared with 56.3, 41, 46.7, and 35 in the control group; in addition, the bupivacaine group required less papaveretum. Twenty four hours after surgery mean values of peak expiratory flow, forced expiratory volume in one second, and forced vital capacity were reduced to 82%, 76%, and 76% of preoperative control values in the bupivacaine group, and to 39%, 32%, and 36% in the control group. The speed of recovery of pulmonary function was superior in the bupivacaine group. There were no complications related to the infusion. Continuous extrapleural intercostal nerve blockade with bupivacaine provides safe and effective postoperative analgesia and improves respiratory mechanics after pleurectomy.

Kairaluoma et al 2004

Single-injection paravertebral block before general anesthesia enhances analgesia after breast cancer surgery with and without associated lymph node biopsy.

Kairaluoma PM, Bachmann MS, Korpinen AK, Rosenberg PH, Pere PJ.

Anesth Analg 2004;99(6):1837–43.

Paravertebral block (PVB) seems to decrease postoperative pain and postoperative nausea and vomiting (PONV) after breast surgery, but the studies have not been placebo controlled. We studied 60 patients scheduled for breast cancer surgery randomly given single-injection PVB at T3 with bupivacaine 5 mg/mL (1.5 mg/kg) or saline before general anesthesia. The patient and attending investigators were blinded; the PVB or the sham block was performed behind a curtain by an anesthesiologist not involved in the study. The patients given PVB with bupivacaine needed 40% less IV opioid medication (primary outcome variable) in the postanesthesia care unit, had a longer latency to the first opioid dose, and had less pain at rest after 24 h than the control patients (P < 0.01). They also had less PONV in the postanesthesia care unit (P < 0.05), were less sedated until 90 min (P < 0.05), and performed better in the digit symbol substitution test at 90 min and the ocular coordination test 60-120 min after surgery (P < 0.05). The average peak bupivacaine plasma concentration was 750 ng/mL. One patient had bilateral convulsions immediately after bupivacaine injection. We conclude that PVB before general anesthesia for breast cancer surgery reduced postoperative pain, opioid consumption, and occurrence of PONV and improved recovery from anesthesia.

Swann et al 1991

The alkalinisation of bupivacaine for intercostal nerve blockade.

Swann DG, Armstrong PJ, Douglas E, Brockway M, Bowler GM.

Anaesthesia 1991;46(3):174–6.

A double-blind randomised study was performed to investigate the effect of pH adjustment of bupivacaine, with adrenaline 1:200,000, on the duration of block and pain relief after intercostal nerve blockade following thoracotomy. One group (n = 10) received bupivacaine with adrenaline 1:200,000 (pH = 4.1) and the other (n = 10) received alkalinised bupivacaine with adrenaline 1:200,000 (pH = 6.9). There was no significant difference in block duration (mean 23.9 and 26.4 hours respectively) visual analogue pain scores or morphine usage. Patients were more likely to have a block during the first 12 hours if they received alkalinised bupivacaine (p less than 0.01, Chi-squared test). A progressive regression of block, not previously described, was observed, explicable by means of spread of local anaesthesia to adjacent intercostal nerves. Alkalinisation of bupivacaine with adrenaline for intercostal nerve blockade has little clinical benefit.

Doyle et al 1998

Pre-emptive effect of multimodal analgesia in thoracic surgery.

Doyle E, Bowler GM.

British Journal of Anaesthesia 1998;80(2):147–51.

Thirty subjects undergoing posterolateral thoracotomy were allocated randomly to receive one of two analgesic regimens: group Pre received i.v. morphine, i.m. diclofenac and intercostal nerve blocks from T2 to T11, 20 min before operation and placebo injections after operation. Group Post received placebo injections before operation, and i.v. morphine, i.m. diclofenac and intercostal nerve blocks from T2 to T11 at the end of surgery, before discontinuation of anaesthesia. Visual analogue pain scores, extent and duration of intercostal nerve block, analgesic consumption and complications were assessed during the postoperative period by a single blinded observer. Subjects were followed-up for a minimum of 12 months to determine the incidence of post-thoracotomy pain syndrome. During the first 48 h after operation there were lower pain scores in group Pre when taking a vital capacity breath but there were no significant differences between the groups in any other measure. The effects of pre-emptive analgesia given before surgery appeared to be relatively modest in terms of analgesia, analgesic consumption and long-term outcome and were of limited clinical significance.

Kavanagh et al 1994

Multimodal analgesia before thoracic surgery does not reduce postoperative pain.

Several reports have suggested that preoperative nociceptive block may reduce postoperative pain, analgesic requirements, or both, beyond the anticipated duration of action of the analgesic agents. We have investigated, in a double-blind, placebo-controlled study, pre-emptive analgesia and the respiratory effects of preoperative administration of a multimodal antinociceptive regimen. Thirty patients undergoing thoracotomy were allocated randomly to two groups. Before surgery, the treatment group (n = 15) received morphine 0.15 mg kg-1 i.m. with perphenazine 0.03 mg kg-1 i.m. and a rectal suppository of indomethacin 100 mg, while the placebo group (n = 15) received midazolam 0.05 mg kg-1 i.m. and a placebo rectal suppository. After induction of anaesthesia, the treatment group received intercostal nerve block with 0.5% bupivacaine and adrenaline 1:200,000 (3 ml) in the interspace of the incision and in the two spaces above and two spaces below. The placebo group received identical injections but with normal saline only. The treatment group consumed significantly less morphine by patient-controlled analgesia in the first 6 h after operation, but the total dose of morphine consumed on days 2 and 3 after surgery was significantly greater in the treatment group. There were no differences between the groups in postoperative VAS scores (at rest or after movement), PaCO2 values or postoperative spirometry. However, pain thresholds to pressure applied at the side of the chest contralateral to the site of incision decreased significantly from preoperative values on days 1 and 2 after surgery in both groups. The results of this study do not support the preoperative use of this combined regimen for post-thoracotomy pain.

Maidatsi et al 1998

Intercostal nerve blockade with a mixture of bupivacaine and phenol enhance the efficacy of intravenous patient-controlled analgesia in the control of post-cholecystectomy pain.

Maidatsi P, Gorgias N, Zaralidou A, Ourailoglou V, Giala M.

Eur J Anaesthesiol 1998;15:529–534.

Shanti et al 2001

Incidence of pneumothorax from intercostal nerve block for analgesia in rib fractures.

Shanti CM, Carlin AM, Tyburski JG.

J Trauma 2001;51(3):536–9.

BACKGROUND: The incidence of pneumothorax (PTX) after individual intercostal nerve block (INB) for postoperative pain reportedly varies from 0.073% to 19%.1-3 This study investigated the incidence of PTX after INB for rib fractures. METHODS: We conducted a retrospective chart review of patients admitted between January 1996 and December 1999 with rib fractures who received INB. RESULTS: One hundred sixty-one patients received 249 intercostal nerve block procedures (INBPs). An INBP is one session where a set of intercostal nerves are blocked. A total of 1,020 individual intercostal nerves were blocked. There were 14 pneumothoraces. The overall incidence of PTX per patient was 8.7%, with an incidence of PTX per INBP of 5.6%. The incidence of PTX was 1.4% for each individual intercostal nerve blocked. CONCLUSION: The incidence of PTX per individual intercostal nerve blocked is low. INB is an effective form of analgesia, and for most patients with rib fractures one INBP is sufficient to allow adequate respiratory exercises and discharge from the hospital.

Cerfolio et al 2003

A prospective, double-blinded, randomized trial evaluating the use of preemptive analgesia of the skin before thoracotomy.

Cerfolio RJ, Bryant AS, Bass CS, Bartolucci AA.

Annals of Thoracic Surgery 2003a;76(4):1055–8.

BACKGROUND: Thoracic surgeons spend a lot of time treating the pain of thoracotomy. METHODS: A total of 119 consecutive patients underwent elective thoracotomy. They were prospectively randomized into two groups. One group received an injection of 1% lidocaine with epinephrine in the planned skin incision just before thoracotomy, and the other group received an equal amount of saline and epinephrine. All patients had a functioning preoperative epidural; a skin incision the width of their latissimus dorsi muscle, which was cut; sparing of the serratus anterior muscle; undercutting of the sixth rib; intercostal nerve blocks before rib spreading; a similar number of chest tubes and pulmonary resections; and comparable postoperative pain management. Pain was objectified by a numeric pain score, a visual pain score, and by the Modified McGill pain questionnaire each day in the hospital, and at 3, 6, and 12 months postoperatively. RESULTS: There were 66 patients in the lidocaine group (L group) and 53 patients in the saline group (S group). Although a trend was noted toward less pain in the L group during the first 3 postoperative days (on the numeric pain scale only) the difference was not statistically significant in overall pain in the hospital or at 3, 6, and 12 months after the operation. Other pain scores and descriptors were similar throughout. CONCLUSIONS: The injection of lidocaine and epinephrine in the skin just before thoracotomy does not decrease the amount or type of pain during the hospital stay or at 3, 6, and 12 months after surgery.

Forty-five adults undergoing thoracotomy were randomized to receive placebo, tenoxicam 20 mg or tenoxicam 40 mg IV during chest wall closure. All patients received intraoperative fentanyl and intercostal blocks followed by morphine by patient-controlled analgesia. Patient numbers 13 to 45 also received thoracic epidural analgesia by continuous infusion of bupivacaine 0.125%, patient numbers 25 to 45 having fentanyl 2 microg/ml added to the epidural infusion. Efficacy parameters and adverse reactions were assessed over the first 24 hours postoperatively. On a 100 mm visual analogue scale, mean (SD) pain at rest (adjusted area under curve for hours 1 to 24) was 25.8 (12.5), 17.4 (14.8) and 16.5 (13.3) mm for groups receiving placebo, 20 mg and 40 mg tenoxicam, respectively (ANOVA: P<0.05). There were no significant differences between study groups postoperatively in pain on coughing, opioid consumption, blood gas measurements, nausea, vomiting, sedation, blood loss, haemoglobin or serum creatinine. One patient in each tenoxicam group reported epigastric pain, rated moderate. These data support the inclusion of tenoxicam 20 mg IV in the management of pain at rest for patients undergoing thoracotomy, but do not show additional benefit for a higher dose.

Baxter et al 1991

A dose-response study of nalbuphine for posthoracotomy epidural analgesia.

Baxter AD, Laganiere S, Samson B, McGilveray IJ, Hull K.

Canadian Journal of Anaesthesia 1991;38(2):175–182.

The analgesic efficacy and side-effects of epidural nalbuphine (0.075-0.3 mg.kg-1) were compared with epidural morphine 0.1 mg.kg-1 in a randomised double-blind study in post-thoracotomy patients. The drugs were administered via a lumbar epidural catheter one hour before the end of surgery. Efficacy was assessed using visual analogue pain scores and supplementary iv fentanyl requirements; respiratory function was studied with an inductive plethysmograph and arterial blood gas analysis; and plasma nalbuphine levels were measured. Pain scores and fentanyl supplementation were lowest in the morphine group (P < 0.01). No dose-response effect was apparent in the nalbuphine dose-range studied. Respiratory depression was more common in patients receiving morphine (higher mean PaCO2P<0.01, more frequent apnoeas > 15 sec P < 0.05, and incidence of PaCO2 > 50 mmHg requiring naloxone P < 0.01). There were no differences in haemodynamic variables, sedation, or other side-effects among the groups. The pharmacokinetic profile of epidural nalbuphine was similar to that seen with rapid iv injection. The results indicate that, relative to morphine, lumbar epidural nalbuphine is an ineffective analgesic after thoracotomy. Despite the lower incidence of respiratory depression its administration by this route cannot be recommended.

Kaplan et al 1975

Postoperative analgesia for thoracotomy patients.

Kaplan JA, Miller ED, Jr., Gallagher EG, Jr.

Anesthesia & Analgesia 1975;54(6):773–7.

Severe postoperative pain, which may persist for up to 3 days and may lead to postoperative complications, due to the patient's inability to breathe deeply and cough, is frequently experienced in the area of the incision and chest tubes by thoracotomy patients. Eighteen patients undergoing routine thoracotomies were tested preoperatively for arterial blood gases and pulmonary function and given chest x-rays. Anesthesia consisted of thiopental, succinylcholine, N2O, enflurane, and pancuronium. Before incision closure, 6 intercostal spaces were injected by the surgeon with 3 ml of a randomly determined drug mixture. Patients received either bupivacaine and saline solution, bupivacaine and LMW dextran 40, or saline and LMW dextran 40. Arterial blood gases, pulmonary function, chest x-rays, narcotic dosage, sensory level, and subjective responses were evaluated for 3 days postoperatively. Results demonstrate that intercostal nerve blocks can markedly reduce postoperative pain and improve pulmonary function in such patients. Significant differences from controls were seen in Pao2, Paco2, vital capacity, forced expiratory flow rates, analgesic requirements, and patient comfort. The duration of the block with bupivacaine and saline was less than 12 hours, while the mean duration of the block with bupivacaine and dextran 40 was 36 hours.

Asantila et al 1986

Comparison of different methods of postoperative analgesia after thoracotomy.

Asantila R, Rosenberg PH, Scheinin B.

Acta Anaesthesiologica Scandinavica 1986;30(6):421–5.

Fifty-one patients scheduled for thoracotomy were included in a study involving five different methods of postoperative analgesia. Forty patients were randomly divided into: Group C, receiving intramuscular oxycodone on request following an intraoperative intercostal block; Group IC, intercostal blocks with 0.5% bupivacaine performed prior to surgery, 6 h later and on the first postoperative morning: Group EB, epidural bupivacaine as a continuous infusion of 0.25% bupivacaine (5 ml h-1); Group EM4 epidural morphine 4 mg injected prior to surgery and on the first postoperative morning. In addition, a fifth group (Group EM6) of 11 patients received 6 mg of epidural morphine timed as in Group EM4, but these patients were automatically scheduled to be observed in the ICU. Additional intramuscular oxycodone was given on request to all patients. Group EB, EM4 and EM6 had lower numbers of requests than Group C. Pain intensity score was lowest (2.5 on a scale from 0 to 10, 3 h postoperatively) in Group EM6, and there was a statistically significant difference in pain intensity at 3 h between EM4 and EM6. The evaluation of cooperation and pain by the physical therapist revealed no differences between the groups. Postoperative blood-gas analyses contained slightly elevated PCO2 values (6.0-7.3 kPa) in all groups. Postoperatively, only Group EB was devoid of PCO2 values above 7.3 kPa. Urinary retention was a common complication in the patients receiving epidural analgesia, occurring most frequently in Group EM6; 10 of the 11 patients had to be catheterized.

Wurnig et al 2002

Is intercostal block for pain management in thoracic surgery more successful than epidural anaesthesia?

OBJECTIVE: Currently epidural anesthesia is the gold standard for postoperative pain management in thoracic surgery. In a prospective randomised study, the effect of an intercostal nerve block applied at the end of the operation was compared to that of epidural anesthesia. METHODS: Thirty patients undergoing thoracotomy were randomised to each group. Patients with resection of the parietal pleura, rib resection and rethoracotomy were excluded from the study. Both groups received non-steroidal anti-inflammatory drugs every 8h as a baseline analgesic medication and were allowed to ask for supplemental subcutaneous opiate injection, limited to four injections per day. The patients in the epidural catheter group (group I) were provided with a motor pump allowing continuous infusion of bupivacain 0.125% and 2mg fentanyl/ml at a dosage of 6-10 ml per hour, dependent on the pain level over a period of 5 days. The patients of the second group (group II) received an intercostal nerve block at the end of the operation reaching from the third to the ninth intercostal space with 20 ml 0.5% bubivacaine. Pain was evaluated with a pain score ranging from 1 (no pain) to 10 (worst pain) twice daily in relaxed position and during physical activity like coughing. On the fifth postoperative day, the patients were asked specific questions concerning the subjective pain experience. Costs of both treatments were calculated. Mean pain values and costs of both groups were compared by t-tests for independent samples. A P value of less than 0.05 was considered significant. RESULTS: Eighteen male and 12 female patients, aged between 35 and 71 years (mean 59) were included in the study. Nineteen patients had lobectomy, five bilobectomy, two decortication and three wedge resection. There were 22 right sided and eight left sided procedures. In group I, the mean pain score on the operation day was 3.95 in relaxed position and 6.33 during physical activity like coughing. The mean pain score during the following 4 days was 2.19 in relaxed position and 4.28 with activity. Three patients required additional subcutaneous opiate injection. In group II, the mean score on the operation day was 2.0 in relaxed position and 3.5 during activity. The mean pain score during the next 4 days was 2.84 in relaxed position and 5.65 with activity. Twelve patients received subcutaneous opiates. In both groups, no complications were observed. COSTS: The costs for treatment of one patient was 105 in group I and 33 in group II. Patients' satisfaction was equal in both groups, there were no differences in terms of outcome and recovery. CONCLUSION: Pain management by intercostal block was superior during the first 24h after surgery whereas on the second day after surgery pain control was significantly better achieved by the epidural catheter in relaxed position. A combination of both forms of anaesthesia seems to be an ideal pain management in patients undergoing thoracic surgery.

Perttunen et al 1995

Forty-five patients were allocated randomly to receive either a single intrathoracic block of four intercostal nerves, a continuous thoracic extradural infusion or a continuous paravertebral infusion of bupivacaine. Patients were allowed additional i.v. boluses of morphine via a PCA device. Segmental spread of pinprick analgesia was comparable in the groups for up to 20 h. Up to 2 h after the block, plasma concentrations of bupivacaine were greater in the intercostal group and there was large interindividual variation. There were no significant differences between the groups in pain, morphine consumption, respiratory function or adverse events. Moderate to severe respiratory depression was detected in 14 patients more than 2 h after operation.

Orr et al 1981

Improved pain relief after thoracotomy: use of cryoprobe and morphine infusion.

Orr IA, Keenan DJ, Dundee JW.

British Medical Journal Clinical Research Ed 1981;283(6297):945–8.

In a randomised controlled trial carried out during the first to days after thoracotomy patients who had had intercostal nerves frozen with a cryoprobe or were given morphine by continuous intravenous infusion had significant less pain at rest than patients given intramuscular morphine. Differences between the groups with respect to pain on movement and during physiotherapy were not significant. Pain was estimated using visual analogue scales, and an arc sine transformation was carried out on values obtained from these scales before comparison using an analysis of variance. The trial did not distinguish between the cryoprobe and infusion treatment. The simplicity of the cryoprobe had much to commend it, but in units without access to this equipment a small infusion pump offers a satisfactory alternative.

Roviaro et al 1986

Intrathoracic intercostal nerve block with phenol in open chest surgery. A randomized study with statistical evaluation of respiratory parameters.

Seventy-three patients who underwent thoracic surgery were randomly selected for intraoperative intercostal nerve block using phenol (32 block and 41 control subjects). The patients were divided into three groups: pneumonectomies, lobectomies and explorative thoracotomies and evaluated by pain level, respiratory function parameters (VT, IRV, ERV, VC) and blood-gas analysis, both six and 24 hrs after surgery. The patients who had intraoperative nerve block using phenol enjoyed a more comfortable postoperative period. In particular, respiratory parameters were statistically better.

OBJECTIVE: To compare the analgesic effects of intrapleural and intravenous morphine administration for postthoracotomy pain management. DESIGN: Randomized, prospective trial. SETTING: University teaching hospital. PARTICIPANTS: Twenty-eight consenting patients scheduled for elective thoracotomy operations. INTERVENTIONS: Patients were randomly allocated into two groups to receive either 20 mg of intrapleural morphine (IPM group) or 20 mg of intravenous morphine (IVM group) at the end of the operation. Plasma morphine levels, arterial pressures, heart rate, verbal analog scale (VAS), respiratory rate, and PaCO2 levels were compared in two groups. MEASUREMENTS AND MAIN RESULTS: Plasma morphine levels were significantly higher in the IVM group at the 5th minute until the 2nd postoperative hour. VAS was significantly higher in the IVM group. Respiratory rates were significantly higher in the IPM group, whereas PaCO2 remained significantly lower than in the IVM group. CONCLUSIONS: IPM achieved better analgesia than IVM and this effect is probably attributable to peripheral effects of morphine.

Brichon et al 1994

Comparison of epidural analgesia and cryoanalgesia in thoracic surgery.

A prospective study was carried out in 120 patients undergoing elective thoracotomy for parenchymal disease. Patients were randomized into three groups: A (control group), B (epidural analgesia), C (freezing of intercostal nerves). Subjective pain relief was assessed on a linear visual analog scale. Analgesic requirements were evaluated during the 12 days following surgery, or until discharge if earlier. The vital capacity (VC) and forced expiratory volume in 1 s (FEV1) were measured on the day before operation and on the 1st, 2nd, 3rd and 7th postoperative days (POD). Subjective pain relief was significantly better in Group B in comparison with Group A (P < 0.05) or C (P < 0.05). Group C had the lowest score on the 11th and 12th POD but differences were not statistically significant. Requirements for intravenous analgesics were lower in Group B than in the control group (P < 0.05) during the first 3 POD, and in group C than in the control group the day of operation (P < 0.05). Oral analgesic requirements, when compared with controls, were lower in group B during the first 5 POD, and lower in group C on the 3rd and the 4th POD (P < 0.05). Cryoanalgesia led to a slight but not significant increase in VC and FEV1. Epidural analgesia led to a significant increase when compared with controls in FEV1 during the first 3 POD, and in FVC on the 7th POD (P < 0.05). It is concluded that epidural analgesia led to the best pain relief and restoration of pulmonary function after thoracotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Keenan et al 1983

Comparative trial of rectal indomethacin and cryoanalgesia for control of early postthoracotomy pain.

Keenan DJ, Cave K, Langdon L, Lea RE.

British Medical Journal Clinical Research Ed 1983;287(6402):1335–7.

A randomised double blind trial was carried out over the first two days after thoracotomy to compare the analgesic effects of rectal indomethacin 100 mg administered eight hourly, cryoanalgesia, and a combination of both of these with the effects of conventional intramuscular opiate analgesia. Pain scores were significantly reduced with both rectal indomethacin alone and cryoanalgesia alone; these treatments had an additive effect when used in combination. Pain on movement was significantly increased, and indomethacin was more effective in reducing this than cryoanalgesia. Groups receiving either indomethacin alone or the combination treatment required significantly less opiate on the first day and exhibited improved peak flow values over the first two days. It is concluded that rectal indomethacin, in this dosage, can provide good, safe analgesia after thoracotomy with minimum administrative difficulty. When used as an adjunct to cryoanalgesia it has an additive effect. There are many potential uses for this drug in other branches of surgery.

Miguel et al 1993

Pain management and spirometry following thoracotomy: a prospective, randomized study of four techniques.

Miguel R, Hubbell D.

Journal of Cardiothoracic & Vascular Anesthesia 1993;7(5):529–34.

Forty-five patients who underwent anterolateral and posterolateral thoracotomy were studied to compare the relative efficacy of cryoanalgesia, epidural morphine, intrapleural analgesia, and intravenous morphine for relief of postoperative pain and prevention of deterioration in pulmonary function. Spirometry (FEV1, FVC) was performed preoperatively and postoperatively. Patients' pain was assessed using the 0 to 100 mm visual analog scale. Because intravenous morphine was used to supplement pain relief in the patients who received intrapleural analgesia and cryoanalgesia, total morphine use was compared to that administered to patients in the intravenous morphine group. Epidural morphine was found to offer better pain relief than the other treatment modalities. There were no differences in spirometric testing between the groups at any time during the study. Although the number of evaluable patients was insufficient to draw definitive conclusions, 12-week follow-up suggested a difference in the incidence of post-thoracotomy pain syndrome in patients who received cryoanalgesia. It is concluded that post-thoracotomy pain is best relieved with epidural morphine, compared to intrapleural analgesia, cryoanalgesia, and parenteral morphine. There was no change in the deterioration in spirometric tests after thoracotomy, nor was there any advantage offered by cryoanalgesia or intrapleural analgesia over intravenous morphine, with respect to pain relief.

Shafei et al 1990

Intrapleural bupivacaine for early post-thoracotomy analgesia--comparison with bupivacaine intercostal block and cryofreezing.

Shafei H, Chamberlain M, Natrajan KN, Khan MA, Gandhi RG

Thoracic & Cardiovascular Surgeon 1990;38(1):38–41.

54 patients who had posterolateral thoracotomy were prospectively studied to compare the efficacy of intrapleural bupivacaine with that of bupivacaine intercostal block and cryofreezing. Patients were randomized into three groups. The intrapleural catheter group included 16 patients who had intermittent intrapleural instillation of 20 ml of 0.25% bupivacaine for forty-eight hours postoperatively. The second group included sixteen patients who were given perioperative bupivacaine intercostal block. The third group included fifteen patients treated by cryofreezing of the intercostal nerves. Visual analogue four-hourly pain score was compared between the three groups during the first forty-eight hours postoperatively. The analgesic requirements during the first postoperative week were also assessed. There was no significant difference between the three groups in the average pain score (3.61 +/- 1.37, 3.54 +/- 1.15, and 3.33 +/- 1.47 respectively). During the first forty-eight hours postoperatively, the percentage of patients who required papaveretum in the intrapleural catheter group (56.3%) was significantly less than that in the other two groups (both 100%). The average papaveretum requirement (mg per patient) in the intrapleural catheter group (27.33 +/- 25.27) was significantly less than that in the second group (52.66 +/- 26.85) but the difference was not statistically significant from that in the third group (37.66 +/- 20.95). No complications related to the use of the intrapleural catheter or to bupivacaine toxicity were encountered. In conclusion, the technique of intermittent intrapleural bupivacaine is safe and comparable in efficacy to bupivacaine intercostal block and cryofreezing. Narcotic requirements may be reduced when this technique is used.

Muller et al 1989

Muller LC, Salzer GM, Ransmayr G, Neiss A.

Annals of Thoracic Surgery 1989;48(1):15–8.

In a randomized study, 63 patients were investigated for the benefits of cryoanalgesia after thoracotomy. Analgesia and its dependent effects such as enhancement of mobility, respiratory function, and reduced need of narcotics were evaluated. No significant differences in these variables were observed between the cryoanalgesia group and the control group. However, moderate to severe neuralgia was found in a number of patients in the cryoanalgesia group in the late postoperative period. Cryoanalgesia for pain relief after thoracotomy is not recommended.

Gough et al 1988

The control of post-thoracotomy pain. A comparative evaluation of thoracic epidural fentanyl infusions and cryo-analgesia.

Gough JD, Williams AB, Vaughan RS, Khalil JF, Butchart EG.

Anaesthesia 1988;43(9):780–3.

This is a comparative study of two methods to relieve postoperative thoracotomy pain. Continuous thoracic epidural infusion of fentanyl produced superior analgesia when compared with cryo-analgesia of the relevant thoracic nerves. Linear analogue pain scores were consistently lower in the epidural group reaching significance (p less than 0.05) at 32 and 40 hours after operation. All 36 patients in the cryo-analgesia group required additional analgesia, while 12 out of the 32 patients in the epidural group did not. This difference was significant at p less than 0.001. Respiratory and cardiovascular measurements were similar in both groups and the only side effect attributable to the epidural fentanyl was itching but this was not a problem.

Khiroya et al 1986

Cryoanalgesia for pain after herniorrhaphy.

Khiroya RC, Davenport HT, Jones JG.

Anaesthesia 1986;41(1):73–76.

The effect of freezing the ilioinguinal nerve on postoperative pain relief was examined in a double blind study in 36 patients undergoing herniorrhaphy, randomly allocated into two groups. Patients in the experimental group had their ilioinguinal nerves frozen during surgery and were compared with the patients in the control group who did not have cryoanalgesia. Pain relief was assessed over a 48-hour period in three ways, namely the linear analogue pain scale, peak expiratory flow rates and the amount of analgesic drugs required by patients in the two groups. We conclude that cryoanalgesia of the ilioinguinal nerve alone does not produce significant early post herniorrhaphy pain relief.

Scawn et al 2001

Ipsilateral shoulder pain after thoracotomy with epidural analgesia: the influence of phrenic nerve infiltration with lidocaine.

Scawn ND, Pennefather SH, Soorae A, Wang JY, Russell GN.

Anesthesia & Analgesia 2001;93(2):260–4.

Patients receiving effective thoracic epidural analgesia for postthoracotomy pain may still complain of severe ipsilateral shoulder pain. The etiology of this pain is unclear. In this randomized, double-blinded, placebo-controlled study, we investigated the effect of phrenic nerve infiltration with lidocaine or saline on postoperative shoulder pain in 48 patients. After completion of a lung resection, patients received either 10 mL of 1% lidocaine or 10 mL of 0.9% saline infiltrated into the periphrenic fat pad at the level of the diaphragm. Shoulder pain was experienced by 33% of patients receiving lidocaine, compared with 85% of patients receiving saline (P < 0.008). Overall pain scores were lower with lidocaine (P < 0.05). PaCO(2) values were not significantly higher with lidocaine in the first 2 h. We conclude that pain transmitted via the phrenic nerve and referred to the shoulder is the most likely explanation for the ipsilateral shoulder pain experienced by patients receiving epidural analgesia for postthoracotomy pain. IMPLICATIONS: Ipsilateral shoulder pain after thoracotomy is common and may be severe, even in the presence of a functioning thoracic epidural. We have shown that infiltration of the phrenic nerve with local anesthetic significantly and safely reduces this shoulder pain, potentially allowing the ideal goal of a pain-free thoracotomy.

Tschernko et al 1996

Postoperative pain is a major cause of ineffective breathing after lung surgery, predisposing patients to hypoxemia. Because potent analgesics like opioids depress ventilation and other analgesic techniques are time-consuming, efficient postoperative pain therapy is difficult. Therefore, a less painful surgical approach could be beneficial. Forty-seven patients with diagnosis of a pulmonary nodule were prospectively studied. Patients were assigned to a video-assisted thoracic surgery (VATS) group (n=22) or a group undergoing axillary thoracotomy (n=25). Visual analogue scale (VAS) scores, plasma glucose levels, plasma epinephrine and plasma norepinephrine levels, as well as arterial oxygen (PaO2) and carbon dioxide (PaCO2) tension were determined the day before surgery, and 3, 15, 24, 48, and 72 h after surgery. Postoperative piritramide (a synthetic morphine compound) demand was recorded. VAS values were significantly lower (p<0.05) during the whole observation period in the VATS group. Significantly higher epinephrine levels were observed 3 and 15 h after surgery (267.4 +/- 28 vs 111.8 +/- 13 ng/L; p<0.01; and 176.6 +/- 46.5 vs 96 +/- 14.5 ng/L; p<0.05) in the thoracotomy group, whereas there was no significant difference in norepinephrine (correction of norephinephrine) levels. Piritramide demand was significantly (p<0.05) reduced in the VATS group throughout the whole observation period. There was no difference in PaCO2 values but PaO2 Values were higher in the VATS group over 72 h, with maximum differences occurring at 15 h after operation: 60.9 +/- 1.9 vs 49.2 +/- 2.4 mm Hg (p<0.01). In conclusion, the videoendoscopic approach is associated with less postoperative pain and better oxygenation than traditional surgical approaches.

Santambrogio et al 1995

Videothoracoscopy versus thoracotomy for the diagnosis of the indeterminate solitary pulmonary nodule.

Santambrogio L, Nosotti M, Bellaviti N, Mezzetti M.

Annals of Thoracic Surgery 1995;59(4):868–70.

The solitary pulmonary nodule often presents a diagnostic challenge to the specialist because the nature of the nodule is often indeterminate at the end of the usual diagnostic process, and operation frequently is required before a definite diagnosis can be made. We have conducted a randomized, prospective trial to evaluate the diagnostic efficacy of video-assisted thoracic surgery versus muscle-sparing lateral thoracotomy. Between January 1991 and May 1994, 44 patients suffering from solitary pulmonary nodule were divided at random into two groups: the nodule was removed in 22 cases by video-assisted thoracic surgery and in 22 cases by lateral thoracotomy. Nineteen wedge resections, 1 segmentectomy, and 2 lobectomies were performed in the first group and 13 wedge resections, 8 segmentectomies, and 1 lobectomy in the second group. An "access" thoracotomy had to be performed in 5 patients in the video-assisted thoracic surgery group. The operating room time was 97.2 +/- 32.9 minutes in the video-assisted thoracic surgery group and 130.5 +/- 14 minutes in the lateral thoracotomy group (p > 0.05). In both groups a final diagnosis was made in 100% of cases. The postoperative hospital stay was 4.6 +/- 1.08 days in the video-assisted thoracic surgery group and 7.8 +/- 0.89 days in the lateral thoracotomy group (p < 0.01). Pain was evaluated on a visual analogue scale; the scores were 26.5 +/- 11.6 in the video-assisted thoracic surgery group and 48.3 +/- 12.8 in the lateral thoracotomy group (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Akcali et al 2003

BACKGROUND: Different alternative approaches to thoracotomy have been developed because of the considerable morbidity associated with the standard posterolateral incision. METHODS: We studied a prospective, randomized, blinded study of 60 consecutive patients to compare surgical approach time, postoperative pain (quantitated by narcotic requirements and the visual analogue scale), pulmonary function, shoulder strength, and range of motion between standard posterolateral (group I) and muscle-sparing (group II) thoracotomy techniques. RESULTS: There were no differences in postoperative surgical time, pulmonary function, shoulder range of motion, mortality, or hospitalization time. There was significantly less postoperative pain in group II. In this group, narcotic requirement was less in the first 24 hours, and visual analogue scale scores were significantly lower (p < 0.05) throughout the first postoperative week. Muscle strength had returned to preoperative levels by 1 month in both groups. Morbidity was identical in the two groups with the exception of postoperative seromas. The prevalence of seroma was 16.6% in the muscle-sparing group. CONCLUSIONS: We conclude that the muscle-sparing incision may be a sensible alternative to a standard posterolateral thoracotomy.

Cerfolio et al 2005

BACKGROUND: Thoracotomy is associated with significant pain and morbidity. METHODS: We performed a prospective randomized trial over 4 months. Patients were randomized to a standard posterior-lateral thoracotomy or an identical procedure, except an intercostal muscle was harvested from the lower rib (to protect the intercostal nerve) before chest retraction. To ensure an equal distribution among both groups, patients were stratified by race, sex, and type of pulmonary resection. All patients received similar pain management. Pain was assessed by using multiple pain scores during hospitalization and after discharge. Outcomes assessed were pain scores, spirometric values, analgesic use, and activity level. RESULTS: There were 114 patients. The median time for intercostal muscle harvesting was 3.7 minutes. The numeric pain scores were lower for the intercostal muscle group on postoperative days 1 and 2 and at weeks 1, 2, 3, 4, 8, and 12 (P < .05 for all). In addition, patients in the intercostal muscle group had a smaller decrease in spirometric values, were less likely to be using analgesics, and were more likely to have returned to normal activity. CONCLUSIONS: The harvesting of an intercostal muscle flap before chest retraction decreases the pain of thoracotomy and leads to a lower decrease in spirometry. In addition, patients have less pain at 1, 2, 3, 4, 8, and 12 weeks postoperatively and are less likely to be using narcotics. Finally, it offers a pedicled muscle flap that takes little time to harvest and is able to buttress all bronchi after lobectomy.

To examine the usefulness of non-serratus-sparing antero-axillary thoracotomy (AAT) with disconnection of anterior rib cartilage for curative resection of lung cancer, we used retrospective analysis to compare mortality, morbidity, hospital stay, time for thoracic opening, postoperative pulmonary function, and chest pain between AAT and posterolateral thoracotomy (PLT). Subjects were 50 lung cancer patients who underwent lobectomy via AAT (n = 25) or PLT (n = 25), who were matched by sex and age. Chest pain was evaluated using a visual analog scale, a McGill pain questionnaire, and analgesic requirements up to 6 months after surgery. AAT offered adequate exposure for lobectomy and mediastinal lymph node dissection. No difference was observed between the AAT and PLT groups in postoperative mortality, morbidity, or hospital stay. Times for thoracic opening were significantly shorter in AAT than in PLT (p < 0.001). FEV1 and vital capacity 1 week after surgery were significantly preserved in patients with AAT compared with patients with PLT (p < 0.05). Chest pain was significantly reduced in AAT patients compared with PLT patients on 1 day and from 14 days to 6 months after surgery (p < 0.01 to p < 0.001). We conclude that AAT is a reasonable thoracotomy alternative to standard PLT for curative lung cancer resection, because of its adequate exposure, shortened opening time, diminished impairment of postoperative pulmonary function, and reduced chronic postoperative pain.

Cerfolio et al 2003b

Intracostal sutures decrease the pain of thoracotomy.

Cerfolio RJ, Price TN, Bryant AS, Sale Bass C, Bartolucci AA.

Annals of Thoracic Surgery 2003b;76(2):407–11

BACKGROUND: General thoracic surgeons spend much time dealing and treating patients' pain after thoracotomy. METHODS: Two hundred eighty consecutive patients underwent elective thoracotomy for pulmonary resection. Patients with a history of chronic pain were excluded. One general thoracic surgeon performed all procedures. All patients had a functioning preoperative epidural, a skin incision the width of their latissimus dorsi muscle which was cut, sparing of the serratus anterior muscle, undercutting of the rib, preemptive analgesia of the intercostal nerve before rib spreading, and similar number of chest tubes and postoperative pain management. The first 140 patients had their chests closed with pericostal sutures (stitches placed on top of the fifth rib and on top of the seventh rib), and the next 140 patients had their chest closed with intracostal sutures (stitches placed on top of the fifth rib and through the small holes drilled in the bed of the sixth rib). Pain was objectified by a numeric pain score and by the McGill pain questionnaire at 2 weeks, and 1, 2, and 3 months postoperatively. RESULTS: There were 140 patients in each group, and the groups were matched for age, gender, race, types of pulmonary resections, number of chest tubes, number of broken ribs, length of chest tube duration, and length of hospital stay (p > 0.05 for all). The mean pain score for the pericostal group (P group) at 2 weeks, 1 month, 2 months, and 3 months postoperatively was 5.5, 3.8, 2.3, and 1.6, respectively. For the intracostal group it was 3.3, 1.7, 1.1, and 0.6, respectively (p = 0.004, p = 0.0001, p < 0.0001, and p < 0.0001, respectively). Descriptors of pain in the P group were more likely to be, hot/burning, shooting or stabbing (p < 0.003). CONCLUSIONS: Intracostal sutures seem to be less painful than pericostal sutures at 2 weeks, 1 month, 2 months, and 3 months after thoracotomy. The pain is less likely to be described as burning or shooting.

Objective: The purpose of this study was to test the hypothesis that after thoracic surgery, the supplementation of a low-dose thoracic epidural (ED) bupivacaine (0.125%) infusion by intravenous (IV) dexmedetomidine decreases analgesic requirement without causing respiratory depression. The primary endpoint was the need for additional ED bupivacaine administered through patient-controlled epidural analgesia (PCEA). Secondary endpoints included the requirement for supplemental opioids and the impact of dexmedetomidine on CO(2) retention. Design: A prospective, randomized, double-blinded study. Setting: A major US tertiary care university hospital. Patients: Twenty-eight patients scheduled to undergo elective thoracotomy for wedge resection, lobectomy, or pneumonectomy. Interventions: On intensive care unit arrival, the thoracic ED catheter was loaded with 0.125% bupivacaine to a T4 sensory level and a continuous infusion of 0.125% bupivacaine without opioid was commenced at 4 mL/h. Patients were then randomized into 1 of 2 groups. The dexmedetomidine group received an IV loading dose of dexmedetomidine of 0.5 mug/kg over 20 minutes, followed by continuous IV infusion at 0.4 mug/kg/h. The placebo group received IV saline at the same calculated loading and infusion rates by volume. If necessary, supplemental analgesia (increased ED rate, ED fentanyl, ketorolac [IV]) was provided to ensure a visual analog scale (VAS) score of </=3. Measurements: The analgesic effect was monitored by the VAS, and the requirement for PCEA dosing and additional analgesics was recorded. Heart rate, blood pressure, and blood gases were also monitored. Main Results: There was no significant difference in PCEA use and VAS score between the 2 groups, but requirement for supplemental ED fentanyl analgesia was significantly greater in the placebo group (66.1 +/- 95.6 v 5.3 +/- 17.1 mug, p = 0.039). Mean PaCO(2) was also significantly greater in the placebo group (40.3 +/- 4.1 v 43.9 +/- 4.3 mmHg, p = 0.04). Patients in the dexmedetomidine group exhibited significantly decreased heart rate (1 patient required and responded to atropine) and blood pressure (4 patients required and readily responded to IV fluid) compared with the placebo group. Conclusion: The authors conclude that in postthoracotomy patients, IV dexmedetomidine is a potentially effective analgesic adjunct to thoracic ED bupivacaine infusion and may decrease the requirement for opioids and potential for respiratory depression.

Martin et al 2003

The role of the alpha2-adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit.

Martin E, Ramsay G, Mantz J, Sum-Ping ST.

J Intensive Care Med 2003;18(1):29–41.

Dexmedetomidine was evaluated for sedation of 401 post-surgical patients in this double-blind, randomized, placebo-controlled, multicenter trial. Dexmedetomidine or saline was started on arrival in the intensive care unit (ICU) (1.0 mcg/kg for 10 minutes), then titrated at 0.2 to 0.7 mcg/kg/h to effect. Patients could be given propofol if necessary. Morphine was administered for pain. Sixty percent of the dexmedetomidine patients required no other sedative to maintain an RSS > or = 3; 21% required < 50 mg propofol. In contrast, 76% of the control group received propofol; 59% required > or = 50 mg. Dexmedetomidine patients required significantly less morphine for pain relief (P <.001). Continuously given throughout the ICU stay, dexmedetomidine had no effect on respiratory rate, oxygen saturation, duration of weaning, or times to extubation. Nurses judged the dexmedetomidine patients were easier to manage. Later, fewer dexmedetomidine patients remembered pain or discomfort. The majority of dexmedetomidine patients maintained blood pressures within normal range, without rebound. Hypertension, atelectasis, and rigors occurred more frequently in the control group, while hypotension and bradycardia occurred more frequently in the dexmedetomidine group. Preoperative cardiovascular conditions were not risk factors for dexmedetomidine patients.

Herr et al 2003

OBJECTIVE: To compare dexmedetomidine-based to propofol-based sedation after coronary artery bypass graft (CABG) surgery in the intensive care unit (ICU). DESIGN: Randomized, open label. SETTING: Twenty-five centers in the United States and Canada. PARTICIPANTS: Two hundred ninety-five adults undergoing CABG surgery. INTERVENTIONS: At sternal closure, patients in group A received 1.0 microg/kg of dexmedetomidine over 20 minutes and then 0.2 to 0.7 microg/kg/h to maintain a Ramsay sedation score > or =3 during assisted ventilation and > or =2 after extubation. Patients could be given propofol for additional sedation if necessary; group B patients received propofol-based care according to each investigator's standard practice. MEASUREMENTS AND MAIN RESULTS: Mean sedation levels were within target ranges in both groups. Mean times to weaning and extubation were similar, although fewer dexmedetomidine patients remained on the ventilator beyond 8 hours. Morphine use was significantly reduced in the dexmedetomidine group. Only 28% of the dexmedetomidine patients required morphine for pain relief while ventilated versus 69% of propofol-based patients (p < 0.001). Propofol patients required 4 times the mean dose of morphine while in the ICU. Mean blood pressure increased initially in both groups, then decreased to 3 mmHg below baseline in dexmedetomidine patients; mean arterial pressure remained at 9 mmHg above baseline in propofol patients. No ventricular tachycardia occurred in the dexmedetomidine-sedated patients compared with 5% of the propofol patients (p = 0.007). Respiratory rates and blood gases were similar. Fewer dexmedetomidine patients received beta-blockers (p = 0.014), antiemetics (p = 0.015), nonsteroidal anti-inflammatory drugs (p < 0.001), epinephrine (p = 0.030), or high-dose diuretics (p < 0.001). CONCLUSION: Dexmedetomidine provided safe and effective sedation for post-CABG surgical patients and significantly reduced the use of analgesics, beta-blockers, antiemetics, epinephrine, and diuretics.

Bigler et al 1992

Effect of piroxicam in addition to continuous thoracic epidural bupivacaine and morphine on postoperative pain and lung function after thoracotomy.

The aim of multimodal analgesic drug therapy in postoperative period is to increase the therapeutic index and to minimise the side effects. The present study was undertaken to assess the efficacy and side effects of the combination of epidural buprenorphine and i.m ketorolac after thoracotomy in immediate postoperative period. In this randomised double blind study, 41 patients were allocated in three groups. Group I (control) received only epidural buprenorphine 150 mug with i.m ketorolac 30 mg respectively, inj ketorolac was given 1 hour after the epidural buprenorphine. Pulse, BP, respiratory rate, arterial blood gases and pain scores were noted intermittently. Groups II and III patients had effective analgesia (pain score < 3) with longer duration (means: 14.1 +/- 2.1 and 9.8 +/- 2.3 hour respectively) than group I (mean :8.7 +/- 2.3 hour). 6 patients in group III were drowsy and 1 required endotracheal intubation. Combination of low dose epidural buprenorphine with i.m ketorolac provides good analgesia without any adverse side effects. However, this technique of combination analgesia needs further evaluation.

BACKGROUND: Post-thoracotomy pain causes severe impairment of the respiratory function. Epidural analgesia is effective in the treatment of post-thoracotomy pain but may give rise to significant side-effects. Other low-risk and cost-effective analgesic treatments are therefore required. METHODS: Thirty male patients who had undergone pulmonary lobectomy entered a prospective, randomized trial to evaluate the efficacy of ketorolac tromethamine (Group 2) and extrapleural intercostal nerve block (Group 3) with intermittent low-dose bupivacaine. Objective and subjective assessment was carried out at 8, 16, 24 and 48 hours postoperatively. RESULTS: There were no significant differences between Groups 1 (control group) and 2. Vital capacity was significantly lower in Group 3 (p<0.05) than in Group 1 after 16 hours. Forced Vital Capacity was significantly higher in Group 2 than in Group 3 after 16 and 24 hours (p<0.05). Peak expiratory flow was also significantly better in Group 2 than in Group 3 after 16 hours (p<0.05). On-demand opioid consumption was significantly lower in Group 2 (p<0.001) and Group 3 (p<0.05). No side-effects were observed. CONCLUSIONS: Ketorolac tromethamine was effective in the treatment of post-thoracotomy pain. Extrapleural intercostal nerve block allowed a significant reduction in the consumption of opioids. These analgesic techniques could be useful as low-risk, cost-effective and reproducible treatments when more effective techniques, such as epidural analgesia, are contraindicated.

Power et al 1994

Ketorolac as a component of balanced analgesia after thoracotomy.

Power I, Bowler GM, Pugh GC, Chambers WA.

British Journal of Anaesthesia 1994;72(2):224–6.

Ketorolac 10 mg or 30 mg i.m., 6 hourly or placebo was given to 75 patients who had undergone thoracotomy, in a randomized double-blind study. All subjects were given intercostal nerve blocks with bupivacaine and had access to i.v. patient-controlled morphine. I.m. ketorolac improved the success rate of the analgesic regimen, with fewer patients withdrawing from the study because of inadequate pain relief.

Perttunen et al 1992

IV diclofenac in post-thoracotomy pain.

Perttunen K, Kalso E, Heinonen J, Salo J.

British Journal of Anaesthesia 1992;68(5):474–80.

We have studied the efficacy of a continuous i.v. infusion of diclofenac 2 mg kg-1/24 h given for 2 days after major thoracic surgery in 30 patients in a double-blind, placebo-controlled, parallel-group design. The patients were able to obtain additional pain relief as on demand morphine boluses. In the diclofenac group, the consumption of morphine was reduced by 60% during the first and by 76% during the second day after operation compared with the control group. Overall, analgesia was also superior in the diclofenac group. Arterial oxygenation was significantly greater and the arterial PCO2 increased less during the first day after operation in the diclofenac group compared with the control group. Diclofenac had no significant effect compared with placebo on blood loss or on any bleeding or platelet test. Urine output was significantly less during the first day after operation in the diclofenac group compared with the control group, but was normal on the second day after operation; plasma creatinine concentrations were unchanged. I.v. diclofenac infusion combined with opioids delivered via a patient-controlled analgesia device seems a valuable method of pain relief after thoracic surgery in patients in whom more invasive techniques, such as extradural local anaesthetics and opioids, cannot be used. However, non-steroidal anti-inflammatory drugs should be used cautiously, if at all, in patients who are at risk of acute renal failure.

McCrory et al 2002

Comparison between repeat bolus intrathecal morphine and an epidurally delivered bupivacaine and fentanyl combination in the management of post-thoracotomy pain with or without cyclooxygenase inhibiti

Tulunay et al 1996

Ketorolac and metomizol in post-thoracotomy pain: A double blind study.

Tulunay M, Tulunay FC, Ozdemir N, Akal M, Yavuzer S, Alkis N.

Turkish Journal of Medical Sciences 1996;26(4):333–338.

The analgesic efficacy and safety of multiple intramuscular injections of 30 mg keterolac were compared with 1000 mg metamizol in a randomized, double-blind study using 60 patients suffering from moderate to very severe pain due to thoracotomy. Patients were administrated the drugs at 2-hour intervals as required, but no more than four times a day. If additional analgesia was required, supplemental analgesic, meperidene 50 mg IM, was permitted. Pain scores were recorded at baseline, 30 minutes, 1 hour, and then hourly for up to 6 hours. Pain relief was measured at the same intervals. 0verall pain intensity and pain relief were also evaluated at 24 and 48 hours. Area under the time-effect curves for pain intensity differences or pain relief revealed that both treatments have similar efficacy. Both the patient's and investigators' final evaluations of efficacy were in favor of metomizol. In addition, the needs of escape medication due to inadequate pain relief were significantly less in the metomizol group. No serious adverse effects were reported. Although, there was no statistical difference in pain measurements between the groups, every trend favored metomizol for postthoracotomy pain.

In a randomized, double-blind, placebo-controlled trial, we assessed the value of adding rectal piroxicam to a low-dose epidural regimen for postoperative pain relief. Forty-four patients scheduled for major upper abdominal surgery during combined thoracic epidural (bupivacaine + morphine) and general anesthesia were studied. Postoperative analgesia was achieved by using epidural bupivacaine (10 mg/h) plus morphine (0.2 mg/h) for 72 h. In addition, the patients randomly received a placebo or rectal piroxicam (40 mg 12 h before surgery, 20 mg with premedication, and 20 mg every 24 h for 72 h). Pain was evaluated every 4 h at rest, during coughing on demand, and during mobilization. The sensory level of analgesia was evaluated by pinprick. We found no significant difference between piroxicam and placebo with regard to postoperative pain scores or need for supplementary analgesics. Thus, we were unable to demonstrate enhanced analgesia by adding piroxicam to an otherwise very effective low-dose epidural bupivacaine and morphine treatment after upper abdominal surgery.

In a double-blind prospective study the effects of low-dose intramuscular ketamine (1 mg/kg) were compared to pethidine (1 mg/kg) in the treatment of pain after pulmonary surgery. Thirty patients were admitted to the study and postoperatively randomized to either a ketamine or a pethidine group. The analgesic effect was evaluated using a scale ranging from 0 to 10, where 0 denoted no pain and 10 severe pain. We did not find any significant difference between the analgesic effect of ketamine and pethidine; however, the duration of action of ketamine appeared to be slightly longer. Throughout the study PaCO2 was significantly lower in the ketamine group. PaO2 increased through the study in both groups and was significantly higher after 2 h. Heart rates increased significantly only in the pethidine group. Mean arterial pressures remained unchanged and the respiratory frequencies were similar in the two groups. The incidence of adverse reactions was low and not significantly different between the groups. The findings indicate that low-dose intramuscular ketamine is a potent analgesic for postoperative analgesia following thoracic surgery and that it has no respiratory depressive effect.

The efficacy of nalbuphine, an agonist/antagonist opioid, in preventing respiratory depression from epidural morphine analgesia after thoracotomy, was assessed in a randomized double-blind placebo controlled trial. After a standardized general anaesthetic and 0.15 mg.kg-1 of epidural morphine, patients received a bolus and then a 24 h infusion of nalbuphine (200 micrograms.kg-1 + 50 micrograms.kg-1.hr-1, 100 micrograms.kg-1 + 25 micrograms.kg-1.hr-1, or 50 micrograms.kg-1 + 12.5 micrograms.kg-1.hr-1) or placebo. Blood gases, analgesia, sedation, side effects, and blood nalbuphine concentrations were assessed every two hours for the next 24 h. Fifty-three per cent of placebo-treated patients had a PaCO2 greater than 50 mmHg and 89 per cent of these received naloxone. A 200 micrograms.kg-1 bolus of nalbuphine followed by a 50 micrograms.kg-1.hr-1 infusion achieved a mean steady state blood level of 38.2 ng.ml-1 and prevented CO2 retention greater than 50 mmHg in all but two patients, neither of whom required naloxone. There was no difference in the incidence of side effects among groups, and analgesia appeared to be unaffected by nalbuphine.

Lehmann et al 1991

Postoperative pain management and respiratory depression after thoracotomy: a comparison of intramuscular piritramide and intravenous patient-controlled analgesia using fentanyl or buprenorphine.

Lehmann KA, Grond S, Freier J, Zech D.

Journal of Clinical Anesthesia 1991;3(3):194–201.

STUDY OBJECTIVE: To compare the analgesic efficacy of fentanyl, buprenorphine, and piritramide and to define the respiratory risk during conventional postoperative pain management and patient-controlled analgesia (PCA). DESIGN: Randomized, single-blind study. SETTING: Department of anesthesiology of an urban hospital. PATIENTS: Sixty patients (ASA) physical status II and III) recovering from unilateral thoracotomy performed under standardized general anesthesia including intercostal blockade. INTERVENTIONS: Patients were treated with intramuscular (IM) piritramide (7.5 to 15 mg as needed) or intravenous (IV) PCA with fentanyl (demand dose 34 micrograms) or buprenorphine (demand dose 80 micrograms) during the early postoperative period, using the On-Demand Analgesia Computer (ODAC, Janssen Scientific Instruments, Beerse, Belgium). MEASUREMENTS AND MAIN RESULTS: The mean postoperative observation period was 24 to 25 hours. During this time, patients requested 55.8 +/- 23.2 mg of piritramide, 1.04 +/- 0.54 mg of fentanyl, or 1.81 +/- 0.78 mg of buprenorphine. Analgesia in all groups was judged mostly good to excellent, with a preference for PCA. Side effects were only of minor intensity in all groups; euphoria or dysphoria occurred only with buprenorphine. Two patients using PCA and five patients having IM analgesia developed short periods of respiratory depression (respiratory rate less than or equal to 8 breaths/minute and/or oxygen (O2) desaturation less than or equal to 90%), which promptly responded to commands to breathe deeply. Respiration rates did not differ, and frequent arterial blood sampling showed normal mean partial pressures of oxygen (PO2) and carbon dioxide (PCO2) and arterial oxygen saturation (SaO2) in all subgroups. CONCLUSIONS: Opioid-induced respiratory depression occurred infrequently during postoperative pain management whether by conventional means or using PCA, even though high doses of opioid analgesics were required intermittently for adequate postoperative pain relief by either technique.

Boulanger et al 1993

Comparison between patient-controlled analgesia and intramuscular meperidine after thoracotomy.

A prospective randomized controlled study was performed to assess the efficacy and safety of patient-controlled analgesia (PCA) in patients undergoing thoracotomy. This method was compared with a conventional pain management technique consisting of regularly scheduled im injections of analgesics. Forty adult patients were randomly assigned to receive intravenous PCA or im meperidine treatment over a 48-hr period after surgery. Care was taken to optimize analgesia in patients of both groups. The McGill Pain Questionnaire, visual analogue and verbal-numeric scales were administered at regular intervals to measure various components of the patients' pain experience, degree of pain relief, adverse side effects and overall treatment efficacy. Functional recovery after surgery was also examined. The results showed good and comparable analgesia with both pain-control methods. However, a greater number of patients receiving im injections required dosage adjustments than in the PCA group. Patients' and nurses' evaluations of overall treatment efficacy also favoured PCA treatment. There were no major group differences in the side effect profile. Recovery pattern was also comparable in the two groups except for the length of hospitalisation. There were fewer long-stay patients in the PCA than in the im group. Meperidine intake was similar in both groups but considerable interpatient variation was seen. In conclusion, PCA is a safe, effective and individualized treatment method for controlling pain after thoracotomy. There appears to be some clinical advantages of PCA over im dosing regimens for analgesia after thoracotomy.

El-Falaki et al 2000

Intravenous patient -controlled fentanyl with and without adaptive background infusion after abdominal hysterectomy.

El-Falaki MM, Abu-hassan KA.

Journal of the Bahrain Medical Society 2000;12(3):139–142.

This study was designed to investigate the post operative quality of analgesia, side effects, patient satisfaction and dose requirements by using intravenous patient controlled fentanyl with and without adaptive background infusion. A prospective study of 20 patients undergoing abdominal hysterectomy are included in the study and divided into two equal groups. Group I received simple patient controlled fentanyl, and Group II received patient controlled fentanyl with adaptive background infusion. Visual analogue score was used to assess the pain and satisfaction. The patients who were given a background infusion had better quality of analgesia and greater satisfaction. No serious side effects were detected with the adaptive background infusion.

BACKGROUND: Many studies have shown the efficacy of patient-controlled analgesia (PCA). However, it is not clear whether PCA has clinical or economic benefits in addition to efficient analgesia. The current study was designed to evaluate these issues by comparing PCA with regularly administered intramuscular injections of opioids after hysterectomy. METHODS: This prospective study included 126 patients who underwent abdominal hysterectomy and were randomly assigned to receive PCA or regularly timed intramuscular injections of morphine during a period of 48 h. Doses were adjusted to provide satisfactory analgesia in both treatment groups. Pain at rest and with movement, functional recovery, drug side effects, and patient satisfaction were measured using rating scales and questionnaires. The costs of PCA and intramuscular therapy were calculated based on personnel time and drug and material requirements. RESULTS: Comparable analgesia was observed with the two treatment methods, with no significant differences in the incidence of side effects or patient satisfaction. The medication dosage had to be adjusted significantly more frequently in the intramuscular group than in the PCA patients. The PCA did not favor a faster recuperation time compared with intramuscular therapy in terms of times to ambulation, resumption of liquid and solid diet, passage of bowel gas, or hospital discharge. The results of the economic evaluation, which used a cost-minimization model and sensitivity analyses, showed that PCA was more costly than regular intramuscular injections despite the fact that no costs for the pump were included in the analyses. Cost differences in nursing time favoring PCA were offset by drug and material costs associated with this type of treatment. CONCLUSIONS: Compared with regularly scheduled intramuscular dosing, PCA is more costly and does not have clinical advantages for pain management after hysterectomy. Because of the comparable outcomes, the general use of PCA in similar patients should be questioned.

Thomas et al 1995

Psychological characteristics and the effectiveness of patient-controlled analgesia.

Thomas V, Heath M, Rose D, Flory P.

Br J Anaesth 1995;74(3):271.

We have evaluated the level of state and trait anxiety, neuroticism, extroversion and coping style as predictors of the effectiveness of patient-controlled analgesia (PCA) in 110 patients undergoing total abdominal hysterectomy. After operation patients were allocated to receive pain control with either PCA or i.m. injections (IMI). Pain was assessed using the short form McGill pain questionnaire at 6, 18 and 24 h after operation, and by recording the amount of analgesic consumed in the first 24 h after surgery. Both state anxiety and coping style were significant predictors of postoperative pain, irrespective of the method of analgesia used. Patients using PCA experienced significantly better pain control than those receiving IMI. However, it was those with high levels of state anxiety who experienced the greatest reduction in pain with PCA. In addition to achieving better pain control, patients who received PCA used significantly less analgesia and were discharged earlier than patients who received IMI.

BACKGROUND: The usefulness of intravenous patient-controlled analgesia (PCA) with opioids for postoperative analgesia is not well defined. METHODS: We systematically searched (MEDLINE, EMBASE, Cochrane Library, bibliographies, any language, to January 2000) for randomised trials comparing opioid-based PCA with the same opioid given intramuscularly, intravenously, or subcutaneously. Weighted mean differences (WMD) for continuous data, relative risks (RR) and numbers-needed-to-treat (NNT) for dichotomous data were calculated with 95% confidence intervals (CI) using fixed and random effects models. RESULTS: Data from 32 trials were analysed: 22 (1139 patients) were with morphine, five (682) with pethidine, three (184) with piritramide, one (47) with nalbuphine and one (20) with tramadol. In three morphine and one pethidine trial (352 patients), more patients preferred PCA (89.7% vs. 65.8%, RR 1.41 (95%CI 1.11 to 1.80), NNT 4.2). Combined dichotomous data on pain intensity and relief, and the need for rescue analgesics from eight morphine, one pethidine, one piritramide, and one nalbuphine trial (691 patients), were in favour of PCA (RR 1.22 (1.00 to 1.50), NNT 8). In two morphine trials (152), pulmonary complications were more frequently prevented with PCA (100% vs. 93.3%, RR 1.07 (1.01 to 1.14), NNT 15). There was equivalence for cumulative opioid consumption, pain scores, duration of hospital stay, and opioid-related adverse effects. CONCLUSION: These trials provide some evidence that in the postoperative pain setting, PCA with opioids, compared with conventional opioid treatment, improve analgesia and decrease the risk of pulmonary complications, and that patients prefer them.

Bloch et al 2002

We compared continuous IV tramadol as an alternative to neuraxial or systemic opioids for the management of postthoracotomy pain in a prospective, randomized, double-blinded, controlled study. General anesthesia was supplemented by thoracic epidural analgesia with 0.25% bupivacaine. At rib approximation, patients received one of the following: IV tramadol (150-mg bolus followed by infusion, total 450 mg/24 h, n = 29), epidural morphine (2 mg, then 0.2 mg/h, n = 30), or patient-controlled analgesia (PCA) morphine only (n = 30). All patients received PCA morphine and rescue morphine as necessary postoperatively. For the first 24 h, pain and sedation scores and respiratory, cardiovascular, and side effect measures were monitored. There was no significant difference in pain scores and PCA morphine use between tramadol and epidural morphine. Pain scores at rest and on coughing were lower in the Tramadol and Epidural Morphine groups than in the PCA Morphine group at various time points over the first 12 h. The Tramadol and Epidural Morphine groups used significantly less hourly PCA morphine than the PCA Morphine group at specific time points in the first 10 h. Vital capacities in the Tramadol group were significantly closer to baseline values at the 20-h point than in the PCA Morphine group. We conclude that an intraoperative bolus of tramadol followed by an infusion was as effective as epidural morphine and avoided the necessity of placing a thoracic epidural catheter. IMPLICATIONS: A prospective, randomized, double-blinded, placebo-controlled study of postthoracotomy pain relief showed that IV tramadol in the form of a bolus followed by continuous infusion was as effective as epidural morphine. The use of tramadol avoids the necessity of placing a thoracic epidural catheter.

Erolcay et al 2003

Intravenous patient-controlled analgesia after thoracotomy: a comparison of morphine with tramadol.

Erolcay H, Yuceyar L.

European Journal of Anaesthesiology 2003;20(2):141–6.

BACKGROUND AND OBJECTIVE: This study examined the quality of analgesia together with the side-effects produced by tramadol compared with morphine using intravenous patient-controlled analgesia during the first 24 h after thoracotomy. METHODS: Forty-four patients scheduled for thoracotomy were included in the study. Morphine 0.3 mg kg(-1) was given interpleurally 20 min before a standard general anaesthetic. In the postanaesthetic care unit, the patients were randomly allocated to one of two groups to self-administer tramadol or morphine using a patient-controlled analgesia device throughout a 24 h period. The patient-controlled analgesia device was programmed to deliver tramadol 20 mg as an intravenous bolus or morphine 2 mg with a lockout time of 10 min. RESULTS: Mean cumulative morphine and tramadol consumption were 48.13 +/- 30.23 and 493.5 +/- 191.5 mg, respectively. There was no difference in the quality of analgesia between groups. Five (26.3%) patients in the tramadol group and seven (33%) in the morphine group had nausea, and three of the latter patients vomited. The incidence rate of vomiting with tramadol was 5.2%. All vital signs were within safe ranges. Sedation was less in the tramadol group, but not statistically significant. CONCLUSIONS: In this clinical setting, which includes interpleural morphine pre-emptively, postoperative analgesia provided by tramadol was similar to that of morphine at rest and during deep inspiration. Side-effects were slight and comparable between the patients receiving morphine and tramadol.

Rømsing et al 2002

Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia.

Rømsing J, Moiniche S, Dahl JB.

Br J Anaesth 2002;88(2):215–226.

BACKGROUND: We have reviewed the analgesic efficacies of rectal and parenteral paracetamol and tested the evidence for a possible additive analgesic effect of the combination of paracetamol with a non-steroidal anti-inflammatory drug (NSAID) in postoperative pain. METHODS: Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia. RESULTS: Eight studies compared rectal paracetamol with placebo. One study of single-dose administration of rectal paracetamol 40–60 mg/kg and three studies of repeat dosing with 14–20 mg/kg showed significant analgesic efficacy, while studies of a single dose of 10–20 mg/kg were negative. Ten studies compared parenteral paracetamol with placebo and eight studies showed improved pain relief with paracetamol. Of the nine studies comparing paracetamol with a combination of paracetamol and an NSAID, six studies showed improved pain relief for the combination while only two of the six studies comparing an NSAID with a combination of an NSAID and paracetamol showed improved pain relief for the combination. CONCLUSIONS: Considering the few studies available, evidence was found of a clinically relevant analgesic effect of rectal and parenteral paracetamol. Concurrent use of paracetamol and an NSAID was superior to paracetamol alone but no evidence was found of superior analgesic effect of the combination compared with the NSAID alone.

Holmer Pettersson et al 2004

Early bioavailability of paracetamol after oral or intravenous administration.

Holmer Pettersson P, Owall A, Jakobsson J.

Acta Anaesthesiol Scand 2004;48(7):867–70.

BACKGROUND: Paracetamol is a peripherally acting analgesic commonly used in multimodal post-operative pain management to reduce the need for more potent analgesics with their unwanted side-effects. The dose and optimal galenical form for achieving analgesic concentrations is not well defined. The primary aim of this pilot project was to study the early bioavailability for two fixed doses of orally administrated paracetamol and one dose of intravenous propacetamol, all of which were given after minor surgery. METHODS: Thirty-five patients undergoing day surgery were divided into five groups, seven patients each. Groups received either 1 g of an ordinary paracetamol tablet, 2 g of an ordinary paracetamol tablet, 1 g of a bicarbonate paracetamol tablet, 2 g of a bicarbonate paracetamol tablet or 2 g intravenously of prodrug propacetamol. We studied the plasma concentration of paracetamol during the first 80 min after administration. RESULTS: Within 40 min, intravenous propacetamol gave a median plasma paracetamol concentration of 85 micromol/l (range 65-161) and decreased thereafter. After oral administration, median plasma paracetamol concentration increased with increasing dose and time, but there were huge inter-individual differences at all time points studied. At 80 min after oral paracetamol the median plasma concentrations were 36 and 129 micromol/l for the 1- and 2-g groups, respectively, with an overall range between 0 and 306 micromol/l. CONCLUSION: Oral administration of paracetamol as part of multimodal pain management immediately post-operatively resulted in a huge and unpredictable variation in plasma concentration compared with the intravenous administration.

Altman 2004

A rationale for combining acetaminophen and NSAIDs for mild-to-moderate pain.

Altman RD.

Clin Exp Rheumatol 2004;22(1):110–7.

Analgesic therapy that combines individual agents with different mechanisms of action has potential advantages for the management of mild-to-moderate pain in the outpatient setting. Theoretically, this approach can lead to greater efficacy and fewer adverse events. While the precise mechanism of action for the analgesic effect of acetaminophen remains uncertain, accumulating evidence suggests that its activity resides primarily in the central nervous system. In contrast, the site of action for the analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is predominantly peripheral, within injured or inflamed tissue. Several controlled clinical studies among patients with musculoskeletal conditions, dental pain, or postoperative pain have shown that combinations of acetaminophen and NSAIDs provide additive pain-relieving activity, thereby leading to dose-sparing effects and improved safety. Further studies are warranted to determine the clinical utility and safety of acetaminophen/NSAID combinations as analgesic therapy for common conditions associated with mild-to-moderate pain.

Azad et al 2000

Objectives: Both continuous epidural analgesia (EA) with local anaesthetics and lipophilic opioids, and patient controlled intravenous analgesia (PCA) with opioids, are techniques routinely used for postoperative pain control. Although both analgesic regimens have been found to provide good analgesia after major surgery, there is still controversy about the superiority of either of the two techniques. The purpose of this study was to compare these two techniques for analgesic efficacy, effect on pulmonary function and incidence of side effects and complications in patients undergoing thoracotomy. Methods: Fifty patients were included in this prospective randomised trial. For postoperative pain control 25 patients (EA group) received thoracic epidural infusion of local anaesthetics (bupivacaine 0.125% or ropivacaine 0.2%) and fentanyl 4.5 mug ml-1 with a flow rate of 4-10 ml h-1. Twenty-five patients received intravenous PCA with piritramid (bolus 2.5 mg, lockout interval of 15 minutes, maximum of 25 mg 4h-1, with no background infusion). Results: Analgesia at rest and while coughing, as evaluated by visual analogue scale (VAS), was significantly better in the EA group. EA also resulted in superior outcome with regard to pulmonary function tests, overall well-being and a lower incidence of sedation and nausea. In contrast, patients with EA reported more pruritus than patients with PCA. The duration of hospital stay was shorter in the EA group, but this difference did not reach statistical significance. No major complications related to EA or PCA were observed. Conclusion: In this study EA with local anaesthetics and fentanyl provided superior postoperative analgesia with a lower incidence of sedation and nausea compared with intravenous opioid PCA, but offered no significant advantages with regard to pulmonary complications and duration of hospital stay.

Boisseau et al 2001

Improvement of 'dynamic analgesia' does not decrease atelectasis after thoracotomy.

There is still controversy concerning the beneficial aspects of 'dynamic analgesia' (i.e. pain while coughing or moving) on the reduction of postoperative atelectasis. In this study, we tested the hypothesis that thoracic epidural analgesia (TEA) prevents these abnormalities as opposed to multimodal analgesia with i.v. patient controlled analgesia (i.v. PCA) after thoracotomy. Fifty-four patients undergoing thoracotomy (lung cancer) were randomly assigned to one of the two groups. Clinical respiratory characteristics, arterial blood gas, and pulmonary function tests (forced vital capacity and forced expiratory volume in 1 s) were obtained before surgery and on the next 3 postoperative days. Atelectasis was compared between the two groups by performing computed tomography (CT) scan of the chest at day 3. Postoperative respiratory function and arterial blood gas values were reduced compared with preoperative values (mean (SD) FEV1 day 0: 1.1 (0.3) litre; 1.3 (0.4) litre) but there was no significant difference between groups at any time. PCA and TEA provided a good level of analgesia at rest (VAS day 0: 21 (15/100); 8 (9/100)), but TEA was more effective for analgesia during mobilization (VAS day 0: 52 (3/100); 25 (17/100)). CT scans revealed comparable amounts of atelectasis (expressed as a percentage of total lung volume) in the TEA (7.1 (2.8)%) and in the i.v. PCA group (6.71 (3.2)%). There was no statistical difference in the number of patients presenting with at least one atelectasis of various types (lamellar, plate, segmental, lobar).

The purpose of this study was to investigate the effect of different pain-relief methods (regional and systemic) following thoracotomies on the cardiovascular system, pulmonary gas exchange, various endocrine parameters and subjective perception. A further aspect was to evaluate the benefits of interpleural analgesia as a new regional technique against already established regional techniques, such as intercostal nerve block and thoracic epidural block. All postoperative pain methods led to a significant time-dependent reduction of the adrenaline concentrations in plasma while the noradrenaline concentrations did not change significantly. There were no statistical differences in catecholamine concentrations among the different study groups, although the mean concentrations of adrenaline in patients having a thoracic epidural block for pain relief were lower in comparison to the findings in other groups. The plasma concentrations of the "stress metabolites", such as glucose, free fatty acids and lactate, as well as the haemodynamic (mean arterial pressure, heart rate) and pulmonary parameters (blood gas analyses), showed no significant differences among groups. In contrast to the other pain-relieving methods, interpleural analgesia did not lead to sufficient pain relief in that 7 out of 10 patients needed supplementary systemic opioid therapy. Therefore, interpleural analgesia for pain relief following thoracotomies cannot be recommended.

Thoracic epidural anesthesia (TEA) combined with general anesthesia (GA) as well as total-IV anesthesia (TIVA) are both established anesthetic managements for thoracic surgery. We compared them with respect to hypoxic pulmonary vasoconstriction, shunt fraction and oxygenation during one-lung ventilation. Fifty patients, ASA physical status II-III undergoing pulmonary resection were randomly allocated to two groups. In the TIVA group, anesthesia was maintained with propofol and fentanyl. In the TEA group, anesthesia was maintained with TEA (bupivacaine 0.5%) combined with low-dose concentration 0.3-0.5 vol% of isoflurane (end-tidal). Changing from two-lung ventilation to one-lung ventilation caused a significant increase in cardiac output (CO) in the TIVA group, whereas no change was observed in the TEA group. One-lung ventilation caused significant increases in shunt fraction in both groups which was associated per definition with a significant decrease in PaO(2) in both groups but PaO(2) remained significantly increased in the TEA group (P < 0.05). We conclude that both anesthetic regimens are safe intraoperatively. However, TEA in combination with GA did not impair arterial oxygenation to the same extent as TIVA, which might be a result of the changes in CO. Therefore, patients with preexisting cardiopulmonary disease and impaired oxygenation before one-lung ventilation might benefit from TEA combined with GA. IMPLICATIONS: Fifty patients underwent lung surgery through the opened chest wall requiring ventilation of only one lung. Patients were randomly assigned to receive either general anesthesia alone or in combination with regional anesthesia via a catheter in the back. Oxygen content in the blood and blood pressure was better maintained in the group receiving the combination of general with regional anesthesia.

George et al 1991

Continuous thoracic epidural fentanyl for post-thoracotomy pain relief: with or without bupivacaine?

George KA, Wright PM, Chisakuta A.

Anaesthesia 1991;46(9):732–6.

Twenty-five ASA 1 or 2 patients undergoing thoracotomy were entered into a prospective, randomised, double-blind study comparing thoracic epidural fentanyl alone and thoracic epidural fentanyl combined with 0.2% bupivacaine. Pain relief, pulmonary function and cardiovascular stability were assessed. Pain relief was superior in the bupivacaine series (p less than 0.05) during the first day after operation and this was accompanied by better oxygenation (p less than 0.05); the difference did not persist into the second day. Forced expiratory variables were reduced in both series to 50-60% of the values before operation throughout the study (p less than 0.05) and differences did not occur between the groups. The incidence of side effects attributable to epidural fentanyl was high, but hypotension did not occur. Small doses of bupivacaine administered together with fentanyl into the thoracic epidural space improve analgesia without causing hypotension.

This study was designed to evaluate the potential fentanyl-sparing effect of a dilute local anesthetic, bupivacaine, administered in fixed combinations with fentanyl for post-thoracotomy analgesia via a continuous thoracic epidural infusion. Forty adult patients scheduled for thoracotomy were randomly allocated in a double-blind fashion to receive an epidural infusion containing 0, 0.03, 0.06, or 0.125% bupivacaine in combination with fentanyl (4 micrograms/mL). The epidural infusions were initiated in the operating room at 10 mL/hr. During the first 24 hours, there were no between-group differences in pain scores. Total fentanyl use was significantly decreased 24% to 33% in all bupivacaine treatment groups. However, fentanyl plasma levels at 24 hours were not significantly different between groups. Arterial blood gas measurements performed on the morning after surgery revealed significant reductions in PaCO2 values, 38 +/- 4, 36 +/- 4, 37 +/- 4 mmHg for 0.03, 0.06, and 0.125% bupivacaine groups respectively, versus 44 +/- 6 for the plain fentanyl group. Arterial pH values were significantly higher in all bupivacaine treatment groups. These findings suggest that the combination of dilute bupivacaine with fentanyl for thoracic epidural analgesia for post-thoracotomy pain may have beneficial effects on pulmonary gas exchange.

Etches et al 1996

Patient-controlled epidural analgesia after thoracotomy: a comparison of meperidine with and without bupivacaine.

Etches RC, Gammer TL, Cornish R.

Anesthesia & Analgesia 1996;83(1):81–6.

The purpose of this study was to compare meperidine to meperidine with bupivacaine when used for patient-controlled epidural analgesia (PCEA) after thoracotomy. For 3 days after thoracotomy patients received thoracic PCEA with meperidine 0.1% plain or with added bupivacaine 0.1% or 0.01%. No background infusion was used. All patients received indomethacin postoperatively for the duration of the study. Patients were assessed with respect to meperidine consumption, analgesia, and side effects. Sixty-six patients participated. Patients in all three groups obtained effective analgesia with median meperidine consumption of 5-6 mg/h. There were no significant differences between groups in meperidine consumption or pain scores at rest or with coughing. The addition of bupivacaine 0.1% reduced the incidence of pruritus (P = 0.036), but 5 of 23 patients in this group were with-drawn from the study because of significant hypotension, oliguria, and/or motor or sensory block (P = 0.006). We conclude that the addition of bupivacaine 0.1% or 0.01% to thoracic PCEA meperidine 0.1% does not affect meperidine requirements or analgesia after thoracotomy. The addition of bupivacaine 0.1% may reduce pruritus, but is associated with signs of excessive sensory, motor, or autonomic blockade in a significant number of patients.

Salomaki et al 1991

This study compared epidural and intravenous fentanyl infusions for pain relief for the first 20 h after thoracotomy, in order to examine whether an thoracic epidural fentanyl infusion offers clinical advantage over an intravenous infusion. Forty patients were assigned randomly to receive either fentanyl epidurally and saline intravenously or fentanyl intravenously and saline epidurally in a double-blind fashion. For each patient the fentanyl infusion was titrated to a rate required for pain relief (pain score less than 3, maximum 10). Patients reported similar median pain scores, but in the epidural group the required mean fentanyl infusion rate was less (0.95 +/- 0.23 vs. 1.67 +/- 0.46 micrograms.kg-1.h-1, P = 0.0001) and plasma fentanyl concentrations were less at 4 and 18 h (4 h: 0.81 +/- 0.27 vs. 1.38 +/- 0.36 ng.ml-1, P = 0.0001; 18 h: 0.94 +/- 0.32 vs. 1.54 +/- 0.65 ng.ml-1, P = 0.0007) than those in the intravenous group. Respiratory function was better preserved and the incidence of nausea and sedation was less in the epidural group than in the intravenous group. In conclusion there appears to be a clinical advantage to the epidural infusion over the intravenous infusion of fentanyl for analgesia after thoracotomy.

In this study the effects of nicomorphine, administered either intramuscularly or by high thoracic epidural route, on the ventilatory and airway occlusion pressure response to CO2 were investigated and compared. Twenty-four patients scheduled for thoracic surgery were allocated randomly to postoperative pain relief by i.m. nicomorphine or by high thoracic epidural nicomorphine. The ventilatory response to 5% carbon dioxide was measured in all patients: first 1 day before operation, secondly on the first day after surgery immediately before nicomorphine administration and finally after the administration, at the moment when no further rise in end-tidal PCO2 (PETCO2) was measured. Respiratory response was assessed in two ways, by measuring minute ventilation (VE) and mouth occlusion pressure (P0.1). There was a significant depression in ventilatory response to CO2 in the intramuscular group (P = 0.03) due to nicomorphine as assessed by the slope of VE vs PETCO2. No significant depression was found in the epidural group, irrespective of measurement of VE or P0.1. No significant shift of apnoeic threshold-PETCO2 was observed in either group.

The authors conducted a prospective, randomized, double-blind comparison of an epidural fentanyl infusion versus patient-controlled analgesia (PCA) with morphine in the management of postthoracotomy pain. Thirty-six patients were randomized into one of two groups. The epidural group received an epidural fentanyl infusion, 10 micrograms/mL, and saline through their PCA machine. The PCA group received an epidural saline infusion and morphine, 1.0 mg/mL, through their PCA device. The infusions were escalated according to a study protocol when pain relief was deemed inadequate by the patients. Pain relief was evaluated by a visual analog pain scale (VAS), both at rest and during coughing, and by verbal rating scores (VRS) of pain relief. Degree of sedation and the frequency of nausea, vomiting, and pruritus were also noted. The VAS, VRS, degree of sedation, and side effects were evaluated every 2 h from 7 AM to 7 PM, for 72 h after surgery. Forced vital capacities were determined before surgery and at 24, 48, and 72 h after surgery. The VAS were significantly lower (P = 0.001), and the Total Pain Relief scores higher (P < 0.02) in the epidural group, signifying better analgesia. There were no differences in postoperative forced vital capacity between the two groups. More patients in the PCA group had greater degrees of sedation on postoperative day 1 (P = 0.005), whereas pruritus was more frequent (P < 0.02) in the epidural group. We conclude that an epidural fentanyl infusion is superior to that of PCA with morphine in the management of pain after thoracotomy.

Larsen et al 1986

Postoperative pain relief and respiratory performance after thoracotomy: a controlled trial comparing the effect of epidural morphine and subcutaneous nicomorphine.

Larsen VH, Christensen P, Brinklov MM, Axelsen F.

Danish Medical Bulletin 1986;33(3):161–4.

Twenty patients scheduled for lateral thoracotomy were randomly allocated to receive either epidural morphine at regular intervals or subcutaneous nicomorphine on demand for postoperative pain relief. The daily dose of opiate administered was greater in the group receiving subcutaneous nicomorphine than in the epidural group although four patients in the latter needed additional subcutaneous injections of opiate. During the first three days of the postoperative course, a profound decrease of the forced vital capacity (FVC), the forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEF) and the arterial oxygen tension (PaO2) was found in both groups, whereas the visual analogue pain score showed a marked increase, and the arterial pH and carbon dioxide tension (PaCO2) remained unchanged. No significant difference could be demonstrated between the group;s. The conclusion is that epidural morphine may produce sufficient pain relief after thoracotomy, but compared with conventional pain treatment the benefits are limited.

El-Baz et al 1984

Continuous epidural infusion of morphine for treatment of pain after thoracic surgery: a new technique.

El-Baz NM, Faber LP, Jensik RJ.

Anesthesia & Analgesia 1984;63(8):757–64.

We evaluated postoperative pain relief and the incidence of side effects of three methods of thoracic epidural analgesia. Ninety patients, divided into three equal groups, received postoperative analgesia after thoracic surgery either as intermittent epidural injections of bupivacaine (25 mg/5 ml, 0.5% solution) as needed, or, intermittent epidural injections of morphine (5 mg/5 ml of normal saline, 0.1% solution) as needed, or continuous epidural infusion of morphine (0.1 mg, in 1 ml of normal saline) per hour supplemented with intravenous morphine (2 mg) upon request. Pain relief was evaluated by each patient on a pain scale visual analogue and by pain relief questionnaire for a period of 72 hr. Postoperative pain relief was achieved equally with these three methods of epidural analgesia in all patients with no significant difference between groups. Intermittent epidural injection of bupivacaine relieved pain for 4.9 +/- 1.9 (SD) hr/injection and was associated with urinary retention in all patients, with numbness and weakness of the hands in 12 patients, and with severe hypotension in 7 patients. Intermittent epidural injection of morphine relieved pain for 5.8 +/- 2.3 hr/injection and was associated with urinary retention in all patients, with pruritus in 12 patients, and with central narcosis and respiratory depression in 8 patients. Continuous epidural infusion of morphine with occasional intravenous morphine (2 mg) supplementation also effectively relieved postoperative pain and was associated with minimal systemic side effects. One patient complained of pruritus, and two patients developed urinary retention.(ABSTRACT TRUNCATED AT 250 WORDS)

Laveaux et al 1993

BACKGROUND AND OBJECTIVES. To compare the postoperative analgesic and side effects of a continuous epidural infusion of bupivacaine with sufentanil: high concentration/low volume versus low concentration/high volume. METHODS. In a prospective study, 30 patients scheduled for thoracic surgery had a thoracic epidural catheter inserted. Postoperative analgesia was provided by a continuous epidural infusion for 3 days. The patients were randomly divided into two groups: the low volume (LV) group (1.5 to 2 mL per hour of a combination of bupivacaine 0.5% with sufentanil 4 micrograms.mL-1) and the high volume (HV) group (6 to 8 mL per hour of a combination of bupivacaine 0.125% with sufentanil 1 microgram.mL-1). RESULTS. The visual analogue scales were not different at rest or with exercise on days 1, 2, or 3. Supplemental analgesia by epidural catheter was necessary in half the patients in both groups. In two patients in the HV group and five patients in the LV group, a PaCO2 greater than mm Hg (7 kPa) was observed the first postoperative hour. Only on day 1 was the mean PaCO2 significantly increased in both groups (5.9 mm Hg [0.7] kPa in the LV group, and 6.0 mm Hg [0.4] kPa in the HV group) compared to the mean preoperative PaCO2 (5.1 mm Hg [0.5] kPa and 4.7 mm Hg [0.6] kPa). Between the groups there was no significant difference in PaCO2 at any time. CONCLUSIONS. With the thoracic epidural administration of bupivacaine and sufentanil for postoperative analgesia, the total dose is more important than the concentration or the volume of the solution.

The purpose of the study was to investigate whether continuous infusion of a high volume of a sufentanil/bupivacaine mixture at a high thoracic level improves the analgesic effect of the mixture, compared with a dose-equivalent continuous low-volume infusion. In a prospective, observer-blind study, 60 patients scheduled for thoracic surgery received a thoracic epidural catheter for 3 days. The patients were randomly assigned by lot to one of two groups: a low-volume (LV) group (bupivacaine 0.75% with sufentanil 4 micrograms/mL, 1.0-1.3 mL/h), or a high-volume (HV) group (bupivacaine 0.125% with sufentanil 0.7 microgram/mL, 6-8 mL/h). On the first postoperative day significantly more patients in the LV group needed one or more epidural bolus injections because they experienced pain at rest (P < 0.05). On the second and third postoperative days there were no differences in bolus injections. Significantly more patients in the HV group did not require an extra epidural bolus injection (P < 0.05). There were no differences in the number of patients experiencing pain at exercise or in the incidence of side effects. A difference was found between both groups in the mean preoperative PaCO2 value (P < 0.05) and also for the PaCO2 values on Day 1 versus the preoperative values within the group (P < 0.05). On the first postoperative day the analgesic effects of a sufentanil/bupivacaine mixture at a high thoracic epidural level can be improved when injected at a continuous high-volume rate compared with a dose-equivalent continuous low-volume rate. This is true for pain at rest; for pain at exercise, there were no differences.

Epidural ropivacaine has not been compared with bupivacaine for postthoracotomy analgesia. Eighty patients undergoing elective lung surgery were randomized in a double-blinded manner to receive one of three solutions for high thoracic epidural analgesia. A continuous epidural infusion of 0.1 mL. kg(-1). h(-1) of either 0.2% ropivacaine, 0.15% ropivacaine/fentanyl 5 micro g/mL, or 0.1% bupivacaine/fentanyl 5 micro g/mL was started at admission to the intensive care unit. We assessed pain scores (rest and spirometry), IV morphine consumption, spirometry, hand grip strength, PaCO(2), heart rate, blood pressure, respiratory rate, and side effects (sedation, nausea, vomiting, and pruritus) for 48 h. Thoracic epidural ropivacaine/fentanyl provided adequate pain relief similar to bupivacaine/fentanyl during the first 2 postoperative days after posterolateral thoracotomy. The use of plain 0.2% ropivacaine was associated with worse pain control during spirometry, larger consumption of IV morphine, and increased incidence of postoperative nausea and vomiting. Morphine requirements were larger in the ropivacaine group, with no differences between bupivacaine/fentanyl and ropivacaine/fentanyl groups. Patients in the ropivacaine group experienced more pain and performed worse in spirometry than patients who received epidural fentanyl. There was no significant difference in motor block. We conclude that epidural ropivacaine/fentanyl offers no clinical advantage compared with bupivacaine/fentanyl for postthoracotomy analgesia. IMPLICATIONS: Thoracic epidural ropivacaine/fentanyl provided adequate pain relief and similar analgesia to bupivacaine/fentanyl during the first 2 postoperative days after posterolateral thoracotomy. Plain 0.2% ropivacaine was associated with worse pain control and an increased incidence of postoperative nausea and vomiting. We conclude that epidural ropivacaine/fentanyl offers no clinical advantage compared with bupivacaine/fentanyl for postthoracotomy analgesia.

Background: Pain relief after thoracotomy can be achieved with thoracic epidural analgesia. The pharmacodynamic profile of ropivacaine was reported to be superior to that of bupivacaine, especially in clinical settings where motor block is undesired. We aimed to compare intermittent thoracic epidural analgesia after thoracotomy using either bupivacaine-fentanyl or ropivacaine-fentanyl. Haemodynamics, ventilation, analgesia and side effects were compared.. Methods: After general Anaesthesia, 30 patients were randomly allocated to receive intermittent epidural bupivacaine 0.25% plus fentanyl 5 [mu]g/ml (n = 15) or ropivacaine 0.25% plus fentanyl 5 [mu]g/ml (n = 15). Heart rate, mean arterial blood pressure, respiratory rate, arterial blood gases were recorded. Motor power, pain score, analgesic requirements and side effects were evaluated over 24 hours postoperatively. Results: Heart rate, arterial blood pressure, respiratory rate and PaCO<inf>2</inf> did not show any between-group differences. At 8 and 12 hours in the recovery room, arterial C<inf>2</inf> tension was significantly higher in RF group than in BF group, with respective values of 141 (29) mm Hg vs. 122 (26) mm Hg and 138 (22) mm Hg vs. 116 (19) mm Hg (P <0.05). Analgesia and diclofenac requirements were comparable in both groups. Motor power of the upper limbs was preserved in both groups. The incidence of side effects did not significantly differ between the two groups. Conclusion: Ropivacaine-fentanyl thoracic epidural analgesia after thoracotomy is comparable to bupivacaine-fentanyl analgesia in terms of pain control and side effects.

Objective. To investigate the efficacy and safety of tetracaine hydrochloride in patient-controlled epidural analgesia (PCEA) after pulmonary lobectomy. Methods. Forty-three patients scheduled for elective pulmonary lobectomy under general anesthesia were randomly allocated into either tetracaine group (22 patients) or ropivacaine group (21 patients). In the tetracaine group, 0.15% tetracaine was used for postoperative PCEA, while 0.3% ropivacaine was used in the ropivacaine group. The duration of postoperative analgesia was 48 h. The PCEA included a bolus of 6 ml with a lockout time of 1 h. Postoperative pain score was measured by visual analogue scale (VAS). Forced expired volume at the 1st second (FEV<inf>1.0</inf>), forced vital capacity (FVC), FEV<inf>1.0</inf>/FVC and peak expired flow (PEF) were measured preoperatively and daily after surgery. Hemodynamics were monitored and recorded before and after each administration of local anesthetics during the period of the study. Results. VAS scores in both groups decreased significantly after a bolus injection of local anesthetics. There was no significant difference between the two groups in VAS either before or after the administration of PCEA. On the 1st and 2nd days after the operation, pulmonary function was reduced in both groups. However, there were no significant differences between the percentage of the changes of FEV<inf>1.0</inf>, FEV<inf>1.0</inf>/FVC and PEF in the two groups. There were also no significant differences between the percentage of the changes of heart rate, mean arterial blood pressure and SpO<inf>2</inf> after administration of local anesthetics. There was no significant difference in overall satisfaction with pain relief. Conclusion. The analgesic effect of 0.15% tetracaine is similar to that of 0.3% ropivacaine used in patient-controlled epidural analgesia after thoracotomy. No serious side effects were observed.

Liu et al 1995b

Effects of epidural bupivacaine after thoracotomy.

Liu S, Angel JM, Owens BD, Carpenter RL, Isabel L.

. Regional Anesthesia 1995b;20(4):303–10.

BACKGROUND AND OBJECTIVES. Combinations of bupivacaine and fentanyl are popular for postoperative epidural analgesia. However, there are little data from which to select a rational dose of bupivacaine. The study examined the effects of increasing amounts of epidural bupivacaine on postoperative analgesia, epidural fentanyl consumption, and side effects after thoracotomy. METHODS. Twenty-four patients were randomized in a double-blind manner to receive intra- and postoperative epidural infusions of either saline, 0.01% bupivacaine, 0.05% bupivacaine, or 0.1% bupivacaine at 10 mL/h. All patients received a standardized combined epidural (120 mg lidocaine and 1.5 micrograms/kg of fentanyl) and general anesthesia. Further postoperative analgesia was provided with fentanyl patient-controlled epidural analgesia (PCEA) only. RESULTS. There were no differences between groups in visual analog scale (VAS) pain scores at rest or cough, but 10 and 5 mg/h of bupivacaine provided better analgesia during physiotherapy (P < .05). The use of 10 and 5 mg/h of bupivacaine led to significant opioid sparing (50% decrease) when compared to saline and 1 mg/h bupivacaine (P < .03). There was a trend toward a greater incidence of orthostasis with the use of bupivacaine at 10 mg/h (P = .09). Incidences of opioid side effects were not different between groups. CONCLUSIONS. The results demonstrate improved analgesia with physiotherapy and significant opioid sparing when 10 and 5 mg/h doses of bupivacaine are used. However, the incidence of orthostasis may be increased with the use of 10 mg/h. Thus, 5 mg/h of epidural bupivacaine (.05% at 10 mL/h) improved analgesia, decreased opioid requirements, and did not have detectable hemodynamic effects.

Geurts et al 1995

Continuous high thoracic epidural administration of morphine with bupivacaine after thoracotomy.

Geurts AM, Jessen HJ, Megens JH, Hasenbos MA, Gielen MJ.

Regional Anesthesia 1995;20(1):27–32.

BACKGROUND AND OBJECTIVES. The purpose of the study is to determine the ideal concentration of morphine when given with bupivacaine as a continuous high thoracic epidural infusion for postthoracotomy pain. METHODS. In a prospective study, 60 patients scheduled for thoracic surgery received a high thoracic epidural catheter. Postoperative analgesia was provided by a continuous epidural infusion for 3 days. The patients were randomly divided into two groups: group 1 (loading dose 1 mg morphine epidurally and continuous infusion of bupivacaine 0.75% + 0.2 mg/mL morphine at an infusion rate of 0.8 mL/hr); group 2 (loading dose 0.5 mg morphine epidurally and continuous infusion of bupivacaine 0.75% + 0.1 mg/mL morphine at an infusion rate of 0.8 mL/hr). RESULTS. The visual analog scales were not different at rest but with exercise in group 1 there was better pain relief than in group 2. The number of patients requiring supplementation of analgesia in group 2 (n = 42) was six times that of group 1 (n = 7). PaCO2 increased in both groups during the first postoperative day. There was no difference in the incidence of side effects between the two groups. CONCLUSIONS. Continuous high thoracic epidural administration 0.2 mg/mL morphine in bupivacaine 0.75% at an infusion rate of 0.8 mL/hr with a loading dose of 1 mg morphine is an effective dose for postthoracotomy pain relief in rest, and more important, during exercise.

Tan et al 2004

Optimal concentration of epidural fentanyl in bupivacaine 0.1% after thoracotomy.

Tan CNH, Guha A, Scawn NDA, Pennefather SH, Russell GN.

British Journal of Anaesthesia 2004;92(5):670–674.

Background. The aim of this prospective, double-blind, randomized controlled trial was to investigate the analgesic and adverse effects of three commonly used concentrations of thoracic epidural fentanyl with bupivacaine in patients undergoing thoracotomy for lung resection. Methods. We studied 99 patients who were randomized to receive fentanyl 2 [mu]g ml<sup>-1</sup> (group 2), fentanyl 5 [mu]g ml<sup>-1</sup> (group 5) and fentanyl 10 [mu]g ml<sup>-1</sup> (group 10) in bupivacaine 0.1% via a thoracic epidural. Postoperatively, pain on coughing was assessed using a visual analogue scale (VAS) and an observer verbal rating score (OVRS) at 2, 8, 16 and 24 h. At the same times, sedation, pruritus and nausea were assessed. Results. Of 29, 28 and 32 patients who completed the study in groups 2, 5 and 10 respectively, there was no significant difference in baseline characteristics between the three groups. The number of patients with episodes of unsatisfactory pain, i.e. VAS scores >30 mm and OVRS > 1, at each of the four assessments postoperatively was significantly (P<0.01) higher in group 2 than in groups 5 and 10. In group 10, 16 patients had sedation scores > 1 compared with 10 each in groups 2 and 5. In addition, 19 patients in group 10 experienced pruritus compared with 12 each, in groups 2 and 5. These differences were not significant. Nausea was not significantly different between the three groups. Conclusion. We conclude that thoracic epidural fentanyl 5 [mu]g ml<sup>-1</sup> with bupivacaine 0.1% provides the optimum balance between pain relief and side effects following thoracotomy. (C) The Board of Management and Trustees of the British Journal of Anaesthesia 2004.

Baxter et al 1994

A comparison of lumbar epidural and intravenous fentanyl infusions for post-thoracotomy analgesia.

Baxter AD, Laganiere S, Samson B, Stewart J, Hull K, Goernert L.

Canadian Journal of Anaesthesia 1994;41(3):184–91

This double-blind randomised study compared the analgesic efficacy, respiratory effects, side effects, and pharmacokinetic disposition of 24 hr lumbar epidural and intravenous infusions of the same dosage regimen of fentanyl (1.5 micrograms.kg-1 bolus then 1 microgram.kg-1.hr-1 infusion) in 50 patients after thoracotomy. Patients received either epidural fentanyl and intravenous normal saline, or epidural normal saline and intravenous fentanyl, for postoperative analgesia, after a standard low-dose alfentanil and isoflurane general anaesthetic. Visual analogue pain scores were lower in the epidural group (P < 0.05) only at two hours postoperatively, and there was no difference in the amount of supplementary morphine self-administered by patient-controlled analgesic pump. A mainly spinal analgesic effect probably occurred in the first few hours since fentanyl was not detectable in the plasma of patients in the epidural group until two hours after bolus injection; its concentration was less at that time than after intravenous injection (P < 0.05). Thereafter there was no difference in the plasma concentration profiles between the two groups. Seven patients in the epidural group and ten patients in the intravenous group received naloxone for PaCO2 > 50 mmHg, and one patient in the intravenous group had the infusions stopped because of PaCO2 elevation and somnolence. In patients who did not receive naloxone, the epidural route produced better analgesia throughout the study period (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-four patients undergoing thoracotomy were entered into a randomized, double-blind, placebo-controlled study to compare the effects of patient-controlled, lumbar epidural (PCA-E) fentanyl with patient-controlled intravenous (PCA-i.v.) fentanyl with respect to drug requirements, analgesic efficacy and respiratory function. Prior to chest closure patients received fentanyl 2 micrograms.kg-1 by the epidural or i.v. route. In the recovery room further doses of epidural or i.v. fentanyl, 50 micrograms, were administered by the patients who controlled two PCA pumps. Background fentanyl infusion rates were increased by 10 micrograms.hr-1 each time the patient administered a drug bolus and were decreased by 10 micrograms.hr-1 whenever visual analogue scale (VAS) pain scores were less than 2 on a maximum 10 scale. Twenty-nine patients completed the study. Patients in the PCA-E group (n = 14) required less total fentanyl than those in the PCA-i.v. (n = 15) group (1857 +/- 693 micrograms vs 2573 +/- 890 micrograms respectively, P less than 0.05). Fentanyl infusion rates were lower in the PCA-E group at most measurement times. There were no differences between groups in respiratory rates, PaCO2, VAS pain scores or changes in pulmonary function as measured by FVC and FEV1. It is concluded that satisfactory patient-controlled analgesia can be achieved with both epidural and i.v. fentanyl after thoracotomy but that fentanyl requirements are less when given via the epidural route. This supports a direct spinal cord site of action for lumbar epidural fentanyl.

Shulman et al 1984

Postthoracotomy pain and pulmonary function following epidural and systemic morphine.

Shulman M, Sandler AN, Bradley JW, Young PS, Brebner J.

Anesthesiology 1984;61(5):569–75.

Thirty patients undergoing thoracotomy for lung resection were entered in a randomized, double-blind trial comparing the effects of epidural (E) versus intravenous (iv) morphine on postoperative pain and pulmonary function. Postoperatively the patients were given repeated doses of either 5.0 mg of morphine epidurally or 0.05-0.07 mg/kg morphine intravenously until there were no further spontaneous complaints of pain. Two, 8, and 24 h postoperatively, the following indices were measured: linear analogue pain score, somnolence score, vital signs, arterial PaO2, PaCO2, and pH, forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow rate (PEFR). Patients receiving epidural morphine had significantly less pain at 2 h (P less than 0.01) and 8 h (P less than 0.004) postoperatively. There was no difference in vital signs except for significantly slower respiratory rates at 2 h (P less than 0.04), 8 h (P less than 0.02) and 24 h (P less than 0.01) in the epidural group. No significant differences occurred in the somnolence scores or blood-gas measurements, which were within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)

Slinger et al 1995

It has remained unclear whether epidural opioid analgesia permits better recovery of postthoracotomy pulmonary function than an optimal method of systemic opioid administration. Lumbar epidural meperidine infusions were compared with intravenous patient-controlled analgesic (PCA) meperidine infusions in a prospective randomized unblinded study for 72 hours postthoracotomy. Before induction of general anesthesia, patients received a bolus of meperidine, 1 mg/kg, and an infusion of meperidine, 0.33 mg/kg/hr, was started via either a lumbar epidural or intravenous catheter. Postoperatively, the meperidine infusion rates were titrated as needed for analgesia. In addition, the intravenous group received meperidine, 10 mg per dose, as required, from a patient-controlled analgesia pump. No other opioid was administered during the study period. Patients were studied for recovery of spirometric tests of pulmonary function, visual analog pain scores, sedation, arterial blood gases, meperidine dose requirements, radiographic pulmonary complications, and neurologic signs and symptoms. A subgroup of 10 patients (5 from each group) had venous blood samples drawn every 24 hours for 96 hours and assayed for serum meperidine and normeperidine concentrations. Epidural meperidine analgesia was associated with improved postthoracotomy pulmonary function, better analgesia scores, and lower meperidine dose requirements than intravenous PCA meperidine. There were no differences between the epidural versus intravenous PCA subgroups with respect to serum meperidine or normeperidine levels. Normeperidine levels greater than 300 ng/mL were associated with an increased incidence of shakiness and/or tremors. Meperidine provides satisfactory postthoracotomy analgesia via a lumbar epidural infusion. This analgesia is associated with improved recovery of postoperative pulmonary function when compared with an intravenous PCA meperidine infusion.

Bouchard et al 1995

BACKGROUND AND OBJECTIVES. Epidural fentanyl injection can provide analgesia following thoracotomy, but where to insert the catheter is a matter of debate. The study compares the effects of thoracic and lumbar patient-controlled epidural fentanyl on analgesia, fentanyl requirements, and plasma levels after thoracotomy. METHODS. Thirty patients were randomized into two groups to receive either thoracic or lumbar patient-controlled epidural fentanyl for postoperative analgesia. Postoperative pain (10 cm, visual analog scale [VAS]) and fentanyl requirements were assessed every 4 hours for 24 hours and at 12-hour intervals for the next day. Fentanyl plasma levels were measured at 8 and 16 hours after surgery. Results were expressed as mean +/- 1 SD and analyzed using Student's t-test, ANOVA, and chi-square analysis at P < .05. RESULTS. Twenty-nine patients completed the study (14 in the lumbar and 15 in the thoracic group). The VAS scores and fentanyl requirements were not significantly different at any time interval in the thoracic group as compared to the lumbar group. VAS scores at 0 hours (4.6) and 4 hours (4.6) in the lumbar group were higher than VAS scores at 12 hours (2.8; P = .04), 16 hours (2.5; P = .02), and 20 hours (2.2; P = .01) in the same group. No significant difference was found between the fentanyl plasma levels of the two groups after 8 hours (lumbar, 0.26 +/- 0.37 ng/mL; thoracic, 0.22 +/- 0.20 ng/mL) or 16 hours (lumbar, 0.36 +/- 0.17 ng/mL; thoracic, 0.44 +/- 0.32 ng/mL). CONCLUSIONS. The authors concluded that there is little if any advantage of thoracic over lumbar patient-controlled epidural fentanyl administration in patients after thoracotomy with respect to analgesia, fentanyl requirements, and plasma levels.

Grant et al 1993

BACKGROUND AND OBJECTIVES. The purpose of this study was to compare the effects of thoracic and lumbar epidural morphine on pulmonary function and analgesia after thoracotomy for pulmonary resection. METHODS. Twenty-seven patients were randomized into two groups to receive either thoracic or lumbar epidural morphine as needed for postoperative analgesia. Postoperative pain was assessed hourly on a 10-cm visual analog scale (VAS), and epidural morphine was administered in 3 mg doses for a VAS score > 2 cm. Patients underwent pulmonary function tests (forced vital capacity, forced expiratory volume at 1 second, peak expiratory flow) preoperatively, and 24 hours postoperatively. Results were expressed as mean +/- 1 SE and analyzed using Student's t-test and Student-Newman-Keuls test at p < 0.05. RESULTS. Twenty patients completed the study (n = 10 per group). Patients in the thoracic group required 3.1 +/- 0.4 injections to a total morphine dose of 11.9 +/- 1.4 mg during the first 24 hours postoperatively, and those in the lumbar group required 4.7 +/- 0.4 doses to a total 24-hour morphine dose of 16.4 +/- 1.2 mg (p < 0.05). Median hourly VAS scores were similar in both groups. Postoperative pulmonary function decreased in both groups without intergroup differences. CONCLUSIONS. The authors conclude that thoracic epidural morphine administration in patients after thoracotomy results in decreased morphine requirements and the same degree of analgesia as does lumbar administration.

Sahin et al 1994

The aim of this study was to investigate whether thoracic epidural administration of a mixture of bupivacaine and fentanyl is superior to lumbar epidural administration for post-thoracotomy pain relief. After informed written consent had been obtained 81 patients who were scheduled for thoracotomy were randomly divided into two groups [group T (n = 50) and group L (n = 31)]. Epidural catheters were placed pre-operatively between the T4-T6 in group T and L1-L4 interspace in group L. At the end of the operation but before skin closure, 10 ml of a prepared solution containing bupivacaine 0.125 per cent and fentanyl 10 mcg/mi were given epidurally to both groups. Following the bolus injection, continuous infusion of the same solution was started at the rate of 6-8 ml/h in group L and 4-6 ml/h in group T. Blood pressure, heart rate, respiratory rate, sedation score, pain score by visual analogue scale and infusion rates were determined at the immediate post-operative period and at 2, 6, 24, 48 and 72 h post-operatively. There were no significant intergroup differences in heart rate, blood pressure, respiratory rate, and sedation score, while infusion and pain score diminished significantly (P < 0.001) in group T. In conclusion thoracic epidural bupivacaine-fentanyl produced much better analgesia than lumbar epidural administration for post-thoracotomy pain relief.

Hurford et al 1993

Comparison of thoracic and lumbar epidural infusions of bupivacaine and fentanyl for post-thoracotomy analgesia.

Hurford WE, Dutton RP, Alfille PH, Clement D, Wilson RS.

Journal of Cardiothoracic & Vascular Anesthesia 1993;7(5):521–5.

Epidural analgesia, via either a thoracic or lumbar route, is commonly used to provide postoperative analgesia following thoracotomy for pulmonary resection, but little data indicate which location is better in terms of postoperative analgesia, side effects, or associated complications. In this study, 45 patients, who were scheduled to have epidural analgesia and undergo a lateral thoracotomy, were randomized to receive either a thoracic or a lumbar catheter. Pain assessments and routine clinical data were recorded to determine if either thoracic or lumbar epidural catheters provided superior analgesia, fewer side effects, or fewer complications. This study found no statistical difference in pain relief or side effects between lumbar and thoracic epidural analgesia for post-thoracotomy pain. An increased infusion rate (6.4 +/- 1.9 v 5.1 +/- 1.4 mL/h, P = 0.02) was required in the lumbar group to achieve equivalent analgesic levels.

Twenty-two patients undergoing thoracotomy were enrolled in a controlled, randomized trial to compare the effects of thoracic (group T) or lumbar (group L) epidural morphine in relieving postoperative pain. Epidural morphine was given as the patient first complained of pain in the recovery room. The effect of epidural morphine on pain relief was assessed by visual analogue scale and subjective grade. All patients were investigated 0, 10, 20, 30, 40, 50, 60, 75, 90, 105 and 120 minutes after a single bolus injection of epidural morphine. In assessment of pain relief by visual analogue scale, the difference between two groups was statistically significant (p < 0.05), evaluated 20, 30 and 40 minutes following treatment. There was no significant difference between two groups with regard to the effect of morphine as assessed by subjective grading. We concluded that thoracic epidural morphine took effect faster than lumbar epidural morphine. However, the effects of both kept similar since 50 minutes after morphine injection.

Radpay et al 2003

Background - Use of narcotics in the epidural space has dramatically changed patient care after surgery because it provides suitable analgesia with fewer complications than other methods. Morphine is a narcotic widely used in the epidural space for pain management, but its use is associated with several complications such as urinary retention, nausea, and vomiting. This study was designed to determine whether the addition of fentanyl to epidural morphine would reduce the associated complications. Methods - Of patients prepared for lung surgery, 72 were selected for epidural analgesia. Twelve patients met the exclusion criteria, but the remaining patients were randomized in a double-blind manner to receive morphine plus fentanyl (n = 30) or morphine alone (control group; n = 30). Drugs were injected when requested by patients, when the visual and verbal pain scores reached 2. Vital signs were checked and complications were recorded in a predefined questionnaire. Results - At the end of the study, there was a higher prevalence of complications in the morphine group than in the morphine plus fentanyl group (p < 0.05). There was no significant difference in analgesic time between the two groups, and analgesic time was more than expected in the morphine plus fentanyl group (p < 0.000). Conclusion - The results of this study showed that adding fentanyl to morphine in epidural analgesia can reduce the complications with at least equal analgesic time. Thus, we can consider this combination as a good choice for epidural analgesia in thoracotomy patients.

Patrick et al 1991

Lumbar epidural diamorphine following thoracic surgery. A comparison of infusion and bolus administration.

Patrick JA, Meyer-Witting M, Reynolds F.

Anaesthesia 1991;46(2):85–9.

Twenty-two patients received a single dose of diamorphine 5 mg through a lumbar epidural catheter before thoracic surgery. The patients were transferred after surgery to a high dependency unit where they were allocated randomly to receive either an infusion of epidural diamorphine at a rate of 1 mg/hour (group 1) or bolus doses of epidural diamorphine 5 mg on demand (group 2). There was no statistically significant difference between the groups in visual analogue pain scores in the first 18 postoperative hours. Arterial carbon dioxide tension was elevated in both groups and was consistently higher in group 1 than in group 2, with a statistically significant intergroup difference 12 hours after operation. Respiratory rate was not a useful index of respiratory depression. The commonest nonrespiratory side effect was urinary retention, but the incidences of this and other minor side effects were similar in the two groups.

After thoracotomy some patients have discomfort, primarily in the rostral portion of their incisions. In this prospective, randomized study in 66 patients after lateral thoracotomy we evaluated whether, for equal fentanyl dosage in micrograms per kilogram, epidural infusion (lumbar catheter) of fentanyl 5 micrograms/mL provided better segmental analgesia (including the rostral portion of the incision) than a 10-micrograms/mL concentration infused at a rate half that used in the 5-micrograms/mL group. Ketorolac was used as an analgesic adjunct for nonincisional pain. Postoperative epidural fentanyl infusion included a 1-microgram/kg initial dose and an initial infusion rate of 1 microgram.kg-1.h-1 in both the 5-micrograms/mL and 10-micrograms/mL groups. Patients were evaluated for comfort level and pain relief while resting, taking a deep breath, coughing, and ambulating at eight times over 3 days using two visual analog scales for overall comfort and a verbal rating score (VRS) for segmental analgesia. There were no significant differences in demographics, surgical procedure, intraoperative fentanyl dose, side effects, rates of epidural fentanyl infusion, or total epidural fentanyl doses at 12, 24, 36, 48, and 60 h postbolus. Analgesia was effective in both groups. Although overall comfort levels were lower (i.e., indicated greater comfort) in the 5-micrograms/mL group in 6 of 8 visual analog scores (VASs) for comfort level and 20 of 24 VRSs for comfort level scores, and mean VRSs for the rostral portion of the incision were lower (i.e., indicated greater comfort) in the 5-micrograms/mL group at 21 of 24 evaluation subsets (one statistically significant), statistical significance was achieved in only six evaluation subsets.(ABSTRACT TRUNCATED AT 250 WORDS)

Whiting et al 1988

Analgesic and respiratory effects of epidural sufentanil in patients following thoracotomy.

Immediately following thoracotomy, 22 patients were entered into a randomized, double blind study comparing the effects of three lumbar epidural doses of sufentanil on postoperative pain and respiratory pattern. Patients were given either 30 micrograms (group I), 50 micrograms (group II), or 75 micrograms (group III) of epidural sufentanil in 20 ml N saline. Repeat doses were given on request for the 24-h study period. Linear analogue pain score (PS), heart rate (HR), and mean arterial pressure (MAP) were measured at 15-min intervals after each dose. Respiratory depression was assessed by the presence of: 1) slow respiratory rate (SRR--less than 10 breaths per minute for greater than 5 min), 2) apnea (AP--cessation of tidal ventilation for greater than 15 s), and 3) increased PaCO2 in arterial blood gases (ABG) drawn at regular intervals. SRR and AP were measured using respiratory inductive plethysmography (RIP). A further group of ten patients (group IV) underwent preoperative RIP monitoring during sleep and in the absence of any drug. Maximum analgesia was achieved within 15 min after a dose of sufentanil for all groups. Analgesia was not significantly prolonged by increasing the dose of sufentanil. SRR occurred in all four groups (group I: 2/9; group II: 2/6; group III: 7/7; group IV: 2/10 P less than 0.05 I, IV:II, I, IV:III, II:III). The number of episodes of SRR/hr was highest in group II (group I: 0.6 +/- 0.8, group II: 4.12 +/- 0.6, group III: 1.8 +/- 2.0, group IV: 0.5 +/- 0.2) (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Etches et al 1991

A comparison of the analgesic and respiratory effects of epidural nalbuphine or morphine in postthoracotomy patients.

Etches RC, Sandler AN, Lawson SL.

Anesthesiology 1991;75(1):9–14.

This randomized, double-blind study compared the analgesic and respiratory effects of lumbar epidural morphine 5 mg, nalbuphine 10 mg, and nalbuphine 20 mg in repeated doses in patients after thoracotomy; the first dose was administered intraoperatively. Pre-and postoperative monitoring included continuous pulse oximetry, respiratory inductance plethysmography, and repeated arterial blood gas analysis. Postoperatively, visual analogue pain scores, somnolence scores, respiratory rate, and arterial blood gases were determined for 16 h. Preoperatively, episodes of apnea were common during sleep but were not associated with low hemoglobin oxygen saturation or increased arterial carbon dioxide tension (PaCO2). During sleep, some otherwise normal patients had increased PaCO2, and 2 of 15 patients had episodes of hemoglobin oxygen saturation of less than 90%. Postoperatively, 1 and 2 h after arrival in the recovery room, patients who received morphine had lower pain scores than did those who received nalbuphine 10 or 20 mg (P less than 0.05). All 6 patients who received morphine had satisfactory analgesia. Two of 4 patients who received nalbuphine 10 mg and all 5 who received nalbuphine 20 mg were withdrawn from the study because of inadequate analgesia (morphine vs. nalbuphine 10 mg, not significant; morphine vs. nalbuphine 20 mg, P less than 0.01). Two patients who received morphine had persistently increased PaCO2 postoperatively. Two patients who received morphine had episodes of apnea and slow respiratory rate, which were most frequent 6 h after arrival in the recovery room. We conclude that lumbar epidural nalbuphine does not provide adequate analgesia after thoracotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Sudarshan et al 1995

Intrathecal fentanyl for post-thoracotomy pain.

Sudarshan G, Browne BL, Matthews JN, Conacher ID.

British Journal of Anaesthesia 1995;75(1):19–22.

This double-blind, placebo-controlled study investigated the efficacy of intermittent doses of intrathecal fentanyl in 30 patients undergoing thoracotomy. They were allocated randomly to three groups, two of which had microspinal catheters inserted into the lumbar subarachnoid space at the end of surgery; the third group acted as a control. Intrathecal fentanyl or 0.9% saline was administered through the catheters and all patients received morphine using a patient-controlled analgesia (PCA) system. Pain scores, morphine consumption and peak expiratory flow rates (PEFR) were recorded on an hourly basis. Intrathecal fentanyl resulted in a faster onset of analgesia (mean visual analogue scale (VAS) score at 1 h = 0.9 compared with 6.3 (95% confidence intervals for the difference -6.8, -4.0) for the other groups; P < 0.001) and significantly lower pain scores at rest, on cough and on movement. PEFR values were consistently higher in the intrathecal fentanyl group. There were no cases of early or delayed respiratory depression.

Barron et al 1999

A randomized controlled trial of continuous extra-pleural analgesia post-thoracotomy: efficacy and choice of local anaesthetic.

Barron DJ, Tolan MJ, Lea RE.

European Journal of Anaesthesiology 1999;16(4):236–45.

Controversy persists over the efficacy of intercostal nerve block administered through a tunnelled extrapleural catheter. We have undertaken a randomized, prospective double-blind trial of two different local anaesthetic regimes to evaluate the effect of this technique on post-thoracotomy pain relief and pulmonary function. Sixty-eight patients were randomized to receive bupivacaine 0.25% (n = 22), lignocaine 1% (n = 21) or 0.9% NaCl (saline) (n = 20) via an extrapleural catheter, inserted peroperatively. All patients underwent a standard posterolateral thoracotomy. Pain was assessed using a visual analogue pain score and by the requirement for opiate analgesia. Pulmonary function was measured using bedside spirometry. Pain scores were lower in the local anaesthetic groups at 24, 32 and 72 h compared with placebo (P < 0.05) and the total amount of opiate required was less than placebo for both lignocaine and bupivicaine (P < 0.05). Pulmonary function was better in the local anaesthetic groups throughout the post-operative period and was most pronounced at 24 h with a mean improvement of 30% for forced expiratory volume (FEV1), 24% for forced vital capacity (FVC) and 19% for peak expiratory flow rate (PEFR) compared with placebo. There was no significant difference between pain scores, opiate requirement or pulmonary function between lignocaine and bupivicaine. CT scanning demonstrated containment of the local anaesthetic in an extra-pleural tunnel. Extra-pleural infusion of local anaesthetics is a simple technique, with low risk of complications and provides effective pain relief as well as an improvement in post-operative pulmonary function. Lignocaine is equally as effective as bupivacaine and its use would result in some cost-saving.

Carabine et al 1995

Pain relief for thoracotomy. Comparison of morphine requirements using an extrapleural infusion of bupivacaine.

Carabine UA, Gilliland H, Johnston JR, McGuigan J.

Regional Anesthesia 1995;20(5):412–7.

BACKGROUND AND OBJECTIVES. The effectiveness of a continuous infusion of extrapleural bupivacaine for relief of postoperative pain was assessed in patients undergoing posterolateral thoracotomy under general anesthesia by comparing morphine requirements. METHODS. Bupivacaine 0.25% was infused at a rate of 5 mL/h through an unkinkable extrapleural catheter that was sited under direct vision at operation. RESULTS. Mean (+/- SD) 24-hour requirements for morphine from a patient-controlled analgesia device were 39 +/- 15 mg for the treated group and 69 +/- 26 mg in the control group (P < .006). Patients in the treated group recorded significantly smaller visual analog scores for pain both at rest (P < .005) and on movement (P < .03) compared to the control group. There were no adverse effects associated with the use of extrapleural bupivacaine in this study. CONCLUSIONS. Continuous extrapleural infusion of bupivacaine through unkinkable catheters sited during thoracotomy resulted in decreased intravenous patient-controlled analgesia use and decreased verbal categoric pain scores at rest and during movement.

OBJECTIVE: To compare continuous thoracic epidural analgesia (TEA) and paravertebral block (PVB) for postoperative analgesia in patients undergoing minimally invasive direct coronary artery bypass (MIDCAB) surgery for quality of analgesia, complications, compliance to chest physiotherapy, hemodynamics, and respiratory effects. DESIGN: Prospective, randomized study. SETTING: Specialty research hospital. PARTICIPANTS: Forty-one consenting patients undergoing MIDCAB surgery. INTERVENTIONS: Patients in the TEA group had an epidural catheter inserted at the T4-5 interspace, whereas patients in the PVB group had a catheter inserted in the paravertebral space on the left side at the T4-5 level. MEASUREMENTS AND MAIN RESULTS: Parameters evaluated included visual analog scale pain scores at rest and while coughing, supplemental analgesic requirement, complications, hemodynamics, and respiratory parameters. Measurements were made at 2-hour intervals for 12 hours beginning at 10 minutes after endotracheal extubation. There was no statistically significant difference in visual analog scale scores and requirement of supplemental analgesia between the 2 groups. Cardiac index at 4 hours and 6 hours was significantly higher in the TEA group. Patients in the PVB group had significantly lower respiratory rates at 8, 10, and 12 hours. All other parameters were comparable. In 1 patient, the epidural space could not be catheterized. One patient in the TEA group had transient hypotension, and 1 patient complained of backache at the site of the epidural catheter insertion. CONCLUSION: PVB is as effective as TEA for postoperative analgesia after MIDCAB surgery. PVB is technically easier than TEA and may be safer than TEA because no complications were seen in the PVB group.

BACKGROUND: Thoracic epidural analgesia is considered the method of choice for postthoracotomy analgesia, but it is not suitable for every patient and is associated with some risks and side effects. We therefore evaluated the effects of an extrapleural intercostal analgesia as an alternative to thoracic epidural analgesia. METHODS: In a prospective, randomized study, pain control, recovery of ventilatory function, and pulmonary complications were analyzed in patients undergoing elective lobectomy or bilobectomy. Two groups of 15 patients each were compared: one received a continuous extrapleural intercostal nerve blockade (T3 through T6) with bupivacaine through an indwelling catheter, the other was administered a combination of local anesthetics (bupivacaine) and opioid analgesics (fentanyl) through a thoracic epidural catheter. RESULTS: Both techniques were safe and highly effective in terms of pain relief and recovery of postoperative pulmonary function. However, minor differences were observed that, together with practical benefits, would favor extrapleural intercostal analgesia. CONCLUSIONS: These results led us to suggest that extrapleural intercostal analgesia might be a valuable alternative to thoracic epidural analgesia for pain control after thoracotomy and should particularly be considered in patients who do not qualify for thoracic epidural analgesia.

Richardson et al 1999

A prospective, randomized comparison of preoperative and continuous balanced epidural or paravertebr

Richardson J, Sabanathan S, Jones J, Shah RD, Cheema S, Mearns AJ.

British Journal of Anaesthesia 1999;83(3):387–92.

Both epidural and paravertebral blocks are effective in controlling post-thoracotomy pain, but comparison of preoperative and balanced techniques, measuring pulmonary function and stress responses, has not been undertaken previously. We studied 100 adult patients, premedicated with morphine and diclofenac, allocated randomly to receive thoracic epidural bupivacaine or thoracic paravertebral bupivacaine as preoperative bolus doses followed by continuous infusions. All patients also received diclofenac and patient-controlled morphine. Significantly lower visual analogue pain scores at rest and on coughing were found in the paravertebral group and patient-controlled morphine requirements were less. Pulmonary function was significantly better preserved in the paravertebral group who had higher oxygen saturations and less postoperative respiratory morbidity. There was a significant increase in plasma concentrations of cortisol from baseline in both the epidural and paravertebral groups and in plasma glucose concentrations in the epidural group, but no significant change from baseline in plasma glucose in the paravertebral group. Areas under the plasma concentration vs time curves for cortisol and glucose were significantly lower in the paravertebral groups. Side effects, especially nausea, vomiting and hypotension, were troublesome only in the epidural group. We conclude that with these regimens, paravertebral block was superior to epidural bupivacaine.

Background - The purpose of this prospective study was to evaluate effects on pain relief, pulmonary function and satisfaction in patients undergoing lung surgery after two different approaches: thoracic epidural analgesia and continuous paravertebral intercostal nerve block. Methods - After obtaining informed consent, 50 patients were randomly assigned to two groups. Postoperative analgesia was performed, by continuous paravertebral infusion of ropivacaine 0.3% in group B and by continuous thoracic epidural infusion of ropivacaine 0.2% plus sufentanyl 0.75 mcg ml<sup>-1</sup> in group A, at a rate of 5 ml h<sup>-1</sup>. Pain was assessed by using visual analogue scale at rest (VASr) and during movements (VASi) within 48h of awakening. We also registered, during the period of the study, blood pressure, heart rate, respiratory rate, oxygen saturation and pulmonary function tests and patient's satisfaction. Results - Analgesia was adequate in either groups: the mean values of VASr were always less than 3 weather mean VASi values were less than 4. Lower VASr values were reached during the first 8 hours in group A compared to group B (p < 0.05). Remaining VASr values were comparable in the two groups. VASi values were also found comparable from 12 to 48 hours after extubation. Patient's satisfaction was significantly better in group B. Minor complications were only found in patients of group A. No differences were found in postoperative hospital stay. Conclusion - Continuous extrapleural intercostals nerve block might be an alternative in patients who have specific contraindication to epidural technique or who refuse the insertion of epidural catheter.

Bimston et al 1999

BACKGROUND: Continuous thoracic epidural analgesia is considered by many the gold standard for post-thoracotomy pain control but is associated with its own complications. In this study we compare continuous paravertebral extrapleural to epidural infusion for post-thoracotomy pain control. METHODS: In a prospective fashion, 50 patients were randomized to receive either paravertebral or epidural infusion for post-thoracotomy pain control. The anesthesia department placed epidurals, and the operative surgeon placed unilateral paravertebral catheters. Patients were evaluated for analgesic efficacy and postoperative complications. RESULTS: We found that both methods of analgesia provide adequate postoperative pain control. Epidural infusion demonstrated an improved efficacy early in the postoperative course but provided statistically similar analgesia to paravertebral by postoperative day 2. Neither group demonstrated a greater number of pain-related complications. Narcotic-induced complications such as pruritus, nausea/vomiting, and postural hypotension/mental status changes/respiratory depression were seen with statistically similar frequency in both epidural and paravertebral arms. Urinary retention, however, was noted to be significantly more frequent in patients with epidural catheters. Drug toxicity was not observed with either epidural or paravertebral infusion. CONCLUSIONS: We recommend continuous paravertebral infusion as an improved method of post-thoracotomy analgesia that can be placed and managed by the surgeon.

Richardson et al 1995

Is laparoscopic hysterectomy a waste of time?

Richardson RE, Bournas N, Magos AL.

Lancet 1995;345(8941):36–41.

Laparoscopic hysterectomy (LH) is a way to avoid laparotomy. However, there is evidence that most women treated by abdominal hysterectomy are suitable for vaginal surgery. To test this hypothesis, and to determine the relative merits of laparoscopic and vaginal hysterectomy (VH) and the best technique for LH, we prospectively studied 98 women who had relative contraindications for vaginal surgery by traditional criteria. 75 underwent LH and 23 VH. The LH group included 22 women who had been assigned to this route of surgery as part of a prospective randomised controlled comparison with VH (23 women). Surgery was completed with the intended technique in 93.9% of cases. 5 women in the LH group (6.7%) and 2 in the VH group required laparotomy or additional procedures. In the prospective randomised study LH took longer than VH (mean duration 131 vs 77 min). VH was the faster procedure, irrespective of uterine size and need for oophorectomy. With LH, the operative time increased as more of the hysterectomy was carried out with laparoscopic rather than vaginal dissection. Complication rates, blood loss, analgesia requirements, and recovery were similar for the two techniques. Our study confirms that most hysterectomies could be performed vaginally, and that LH is a much slower procedure. If LH is done, it should be converted to a vaginal procedure as early as possible to reduce the overall operating time. LH does seem to be a waste of time for most patients.

Davies et al 2006

A comparison of the analgesic efficacy and side-effects of paravertebral vs epidural blockade for thoracotomy--a systematic review and meta-analysis of randomized trials.

Davies RG, Myles PS, Graham JM.

Br J Anaesth 2006; 96(4):418–26.

Epidural analgesia is considered by many to be the best method of pain relief after major surgery. It is used routinely in many thoracic surgery centres. Although effective, side-effects include hypotension, urinary retention, incomplete (or failed) block, and, in rare cases, paraplegia. Paravertebral block (PVB) is an alternative technique that may offer comparable analgesic effectiveness and a better side-effect profile. We undertook a systematic review and meta-analysis of all relevant randomized trials comparing PVB with epidural analgesia in thoracic surgery. Data were abstracted and verified by both authors. Studies were tested for heterogeneity, and meta-analyses were done with random effects or fixed effects models. Weighted mean difference (WMD) was used for numerical outcomes and odds ratio (OR) for dichotomous outcomes, both with 95% CI. We identified 10 trials that had enrolled 520 thoracic surgery patients. All of the trials were small (n<130) and none were blinded. There was no significant difference between PVB and epidural groups for pain scores at 4-8, 24 or 48 h, WMD 0.37 (95% CI: -0.5, 121), 0.05 (-0.6, 0.7), -0.04 (-0.4, 0.3), respectively. Pulmonary complications occurred less often with PVB, OR 0.36 (0.14, 0.92). Urinary retention, OR 0.23 (0.10, 0.51), nausea and vomiting, OR 0.47 (0.24, 0.53), and hypotension, OR 0.23 (0.11, 0.48), were less common with PVB. Rates of failed block were lower in the PVB group, OR 0.28 (0.2, 0.6). PVB and epidural analgesia provide comparable pain relief after thoracic surgery, but PVB has a better side-effect profile and is associated with a reduction in pulmonary complications. PVB can be recommended for major thoracic surgery.

Richardson et al 1995

A prospective, randomized comparison of interpleural and paravertebral analgesia in thoracic surgery.

Richardson J, Sabanathan S, Mearns AJ, Shah RD, Goulden C.

British Journal of Anaesthesia 1995;75(4):405–8.

We have undertaken a prospective, randomized comparison of the superficially similar techniques of interpleural and paravertebral (extrapleural) analgesia in 53 patients undergoing posterolateral thoracotomy. Local anaesthetic placed anterior to the superior costotransverse ligament and posterior to the parietal pleura produces a paravertebral block and instilled between the parietal and visceral pleurae produces an interpleural block. Patients received preoperative and postoperative continuous bupivacaine paravertebral blocks in group 1 and interpleural blocks in group 2. Premedication comprised diclofenac and morphine, and after operation all patients had regular diclofenac and patient-controlled morphine (PCM). Analgesia was assessed by visual analogue pain scores (VAS), PCM requirements, ratio of preoperative to postoperative spirometric values (PFT), rates of postoperative respiratory morbidity (PORM) and hospital stay, all recorded by blinded observers. Eight patients were withdrawn and data from 45 patients were analysed. Patient characteristics, surgery, VAS scores and PCM use were similar in both groups. PFT were significantly better (P = 0.03-0.0001) in group 1, and PORM was lower and hospital stay approximately 1 day less in this group. Five patients in group 2 became temporarily confused, probably because of bupivacaine toxicity (P = 0.02). We conclude that bupivacaine deposited paravertebrally produced greater preservation of lung function and fewer side effects than bupivacaine administered interpleurally.

Wedad et al 2004

The effect of addition of wound infiltration with local anaesthetics to interpleural block on post-thoracotomy pain, pulmonary function and stress response in comparison to thoracic epidural and parav

Wedad M, Zaki MK, Haleem M.

Egyptian Journal of Anaesthesia 2004;20(1):67–72.

Egyptian Journal of Anaesthesia 2004;20(1):67–72.Background: This study was carried out to compare the efficacy of 3 local anaesthetic techniques to control post-thoracotomy pain and their effect on pulmonary functions and stress response. Methods: Sixty adult patients, aged 25-65 years, ASA status I-III, undergoing lateral thoracotomy for lower oesophageal surgeries were studied. They were divided randomly into 3 equal groups (n = 20 each): group I (thoracic epidural group), group II (paravertebral group) and group III (interpleural block with wound infiltration). Subjective pain relief was assessed by visual analogue scale. Pulmonary functions were assessed by FVC, FEV<inf>1</inf>, and PEFR. Stress response was assessed by measurement of plasma glucose and cortisol levels. Results: The results of this study showed that in the first postoperative day, pulmonary function tests were best in group II, while groups I and III were comparable. In the 2nd postoperative day, group II also had the best pulmonary functions, while group III had the worst pulmonary functions. VAS scores were least in group II. Also, the narcotic consumption was least in group II, which also showed the least increase in glucose and cortisol levels. Conclusion: It was concluded that paravertebral block is the best method for post-thoracotomy pain relief and that the addition of wound infiltration to interpleural block improved markedly the pain relief of this technique in the first postoperative day. This combination was comparable to extradural block with more preservation of pulmonary functions.

Twenty patients undergoing elective thoracotomy were randomized into two groups, receiving either lumbar epidural morphine (n = 10) or continuous extrapleural intercostal nerve block (n = 10). Subjective pain relief was assessed on a linear visual analogue scale. Pulmonary function (peak expiratory flow rate, forced expiratory volume in 1 second, and forced vital capacity) was measured on the day before operation and daily for 4 days after operation. Pulse oximetry monitoring was used to determine the incidence of hypoxemia. No significant difference was observed between the groups concerning pain relief (except at 28 hours, in favor of the intercostal nerve block group), respiratory performance, or arterial oxygen saturation. Vomiting, pruritus, and urinary retention occurred only in the epidural group, whereas nausea occurred significantly less frequently in the extrapleural group. We conclude that after thoracotomy continuous extrapleural intercostal nerve block is as effective as lumbar epidural morphine in reducing postoperative pain and restoring pulmonary mechanics. Because of the significantly lower complication rates we favor continuous extrapleural intercostal nerve block for postthoracotomy analgesia.

Catala et al 1996

Continuous infusion is superior to bolus doses with thoracic paravertebral blocks after thoracotomies.

Catala E, Casas JI, Unzueta MC, Diaz X, Aliaga L, Villar Landeira JM.

Journal of Cardiothoracic & Vascular Anesthesia 1996;10(5):586–8.

OBJECTIVES: This study was designed to determine whether a continuous thoracic paravertebral infusion of bupivacaine (continuous TPVI) offers a higher quality of analgesia than a bolus regimen after thoracotomy. DESIGN: A prospective and randomized study. SETTING: It was conducted by an anesthesiology and pain clinic department in a university hospital. PARTICIPANTS: Thirty patients were included in this study. INTERVENTIONS: As postoperative analgesia, the patients received either 20 mL of 0.375% bupivacaine every 6 hours (n = 15; bolus group), or a loading dose of 15 mL of 0.375% bupivacaine, plus an infusion of 5 mL of 0.25% bupivacaine every hour (n = 15; infusion group). MEASUREMENTS AND MAIN RESULTS: Pain intensity was assessed at rest and on movement (coughing) at 0, 1, 4, 10, 20, and 48 hours by means of the visual analog scale. The need for additional rescue analgesia, bupivacaine plasma concentration in the infusion group, blockade level (pinprick), and vital signs were also recorded. There were no significant differences regarding the additional rescue analgesia, vital signs, and pinprick level. However, the pain scores were significantly higher in the bolus group at rest and on movement (p < 0.01). The bupivacaine plasma concentration was low with a Cmax of 1.841 +/- 0.20 micrograms/mL at 15 hours. No systemic toxicity or other side effects were seen. CONCLUSION: Results suggest that continuous TPVI provides better pain control than the bolus regimen after this kind of surgery.

Gamal et al 2003

Background: Thoracic paravertebral block is effective in controlling post-thoracotomy pain, but the use of the optimum concentration of ropivacaine, has not been determined previously. Methods: This study was done on 60 patients undergoing thoracotomy. Patients were allocated randomly into three equal groups to receive continuous thoracic paravertebral ropivacaine in three concentrations: 0.25%, 0.375%, and 0.5%. Pain scores at rest, on coughing and patient-controlled intravenous morphine requirements were measured. Plasma concentrations of ropivacaine and peak expiratory flow rate (PEFR) were also measured and side effects were recorded. Results: There was significantly lower visual analogue pain scores at rest, on coughing, and patient-controlled morphine requirements were less in the 0.5% ropivacaine group [32.1 (5.1) mg, 51.3 (5.2) mg at 24 h and 48 h, respectively]. There was a significant increase in plasma concentrations of ropivacaine in the 0.5% ropivacaine group [5.1 (2.2) [mu]g/ml]; however, there was no signs or symptoms of toxicity observed. PEFR was better preserved in the 0.5% ropivacaine group. Nausea and vomiting were significantly higher in the 0.25% and 0.375% ropivacaine groups. Conclusion: Continuous thoracic paravertebral block with ropivacaine 0.5% is an effective and safe for post-thoracotomy pain relief.

Dryden et al 1993

Efficacy of continuous intercostal bupivacaine for pain relief after thoracotomy.

Dryden CM, McMenemin I, Duthie DJ.

British Journal of Anaesthesia 1993;70(5):508–10.

We studied 20 patients undergoing thoracotomy, in a double-blind, placebo-controlled crossover trial of intercostal bupivacaine. Bupivacaine 0.25% was infused at 5 ml h-1 through each of two catheters placed in the intercostal space at operation. Mean (95% confidence limits) 24-h requirements for morphine from a patient-controlled analgesia device were 29 (22-37) mg during bupivacaine infusion and 44 (32-57) mg during saline infusion (P = 0.04). Patients also recorded significantly smaller visual analogue scores for pain during bupivacaine infusion. There were no adverse effects related to the intercostal infusion of bupivacaine. We conclude that bupivacaine, infused through catheters placed during thoracotomy in the adjacent intercostal spaces, is a useful adjunct to systemic opioid analgesia.

BACKGROUND: Pain following thoracotomy is frequently associated with clinically important abnormalities of pulmonary function. The aim of the current study was to compare the efficacy of continuous thoracic epidural analgesia (EDA) to continuous intercostal (IC) block for postoperative pain and pulmonary function in a prospective, randomized, double-blinded clinical trial. METHODS: Fifty patients undergoing lung lobectomy for malignancies were randomized into two groups (25/group). Respiratory function (forced vital capacity, forced expiratory volume per 1 s/forced vital capacity, maximum midexpiratory flow rate, peak expiratory flow rate) were evaluated preoperatively, within 4 h after the operation and on the first postoperative day. Visual analog scale (VAS: 0-10) scores were evaluated four-hourly for 20 h. RESULTS: The VAS scores were significantly lower in the EDA versus IC group at the 4th, 8th, and 12th h of observation (mean +/- SD) 5.5 +/- 2.9 vs. 7.3 +/- 2.2 P = 0.04; 4.1 +/- 2.1 vs. 5.1 +/- 2.9 P = 0.02; 3.6 +/- 1.9 vs. 5.2 +/- 2.4 P = 0.01, respectively. Respiratory function parameters deteriorated significantly in both groups (P < 0.001) with no significant difference between the groups. Only one major adverse effect was detected: one patient suffered from rib osteomyelitis after intercostal cannulation and healed following surgical repair. CONCLUSIONS: The results of the present study show that following thoracotomy in the early postoperative period continuous EDA is a better pain relieving method than continuous IC block, as indicated by the VAS scores.

Scheinin et al 1987b

Sympatho-adrenal and pituitary hormone responses during and immediately after thoracic surgery--modulation by four different pain treatments.

Scheinin B, Scheinin M, Asantila R, Lindberg R, Viinamaki O.

Acta Anaesthesiologica Scandinavica 1987b;31(8):762–7.

Four different pain treatments (single intercostal block with bupivacaine, repeated intercostal block, epidural morphine and epidural bupivacaine infusions) were compared in 39 patients subjected to lung surgery under general anaesthesia. The patients' own estimate of the postoperative pain was not significantly different between the groups, but the epidurally treated patients required fewer doses of supplementary analgesic than those given just a single dose of intercostal bupivacaine. Bupivacaine levels in blood were below the toxic range in all groups. The concentration of antidiuretic hormone in blood was increased early during the operation, and had only partly returned to normal on the first postoperative morning. Growth hormone in plasma was increased only at the end of the operation. Catecholamine levels in blood increased gradually, reaching their peak postoperatively. There were only slight differences between the groups in these posterior and anterior pituitary and sympatho-adrenal responses to surgical stress. Thus, neither repeated intercostal blockade nor epidural administration of morphine or bupivacaine could prevent the endocrine responses to thoracic surgery, in spite of significant, albeit incomplete, pain relief. This was probably caused in part by residual pain, and also by poor access of the extradural medications to the autonomic afferent pathways mediating nociceptive signals from thoracic organs and tissues.

Broome et al 1993

This study examined the effectiveness of a new type of chest drain, which incorporates an additional lumen within its wall to facilitate the administration of intrapleural bupivacaine. Nine patients who received a bolus dose of 1.5 mg.kg-1 bupivacaine with 1:200,000 adrenaline through this chest drain used less morphine, and had lower visual analogue pain scores in the first 6 h after thoracotomy than patients in whom a standard chest drain had been used. Bupivacaine levels were found to be within safe limits in all patients.

Symreng et al 1989

The effects of intrapleural (IP) bupivacaine on pain, morphine requirement, and pulmonary function were evaluated in 15 patients for 24 hours after thoracotomy. An IP catheter was placed during surgery. Patients were randomized in a double-blind fashion to receive 1.5 mg/kg of 0.5% bupivacaine IP or saline on two occasions, eight hours apart. A standard anesthetic with thiopental, oxygen, isoflurane, and nondepolarizing muscle relaxant was given. Pain was evaluated with a visual analog pain score every hour, and forced vital capacity (FVC), forced expiratory volume one second (FEV1), peak expiratory flow (PF), and forced expiratory flow 25% to 75% (FEF) were measured 1, 2, 4, 8, and 24 hours postoperatively as well as before and 30 minutes after each IP injection. Arterial blood gases were sampled 1, 2, 8, and 24 hours postoperatively. Plasma bupivacaine concentrations were measured in 10 patients 5, 10, 20, 30, 60, 120, and 180 minutes after IP injection. With each IP bupivacaine injection, the pain score and morphine requirement decreased. There was a significant improvement in all pulmonary function tests in the patients receiving bupivacaine, but no change in the saline controls. The analgesic effect was shortlived (two to five hours), possibly because of loss of bupivacaine in the chest drains. No differences were seen between the two groups after the effect of IP bupivacaine had worn off. Plasma bupivacaine levels had a Cmax of 0.44 to 1.50 micrograms/mL, with a Tmax at 5 to 30 minutes with levels well below 2 to 4 micrograms/mL where increasing toxicity is seen.

The value of intrapleural analgesia after thoracotomy is still controversial. We investigated the pharmacokinetics of interpleural analgesia in 14 patients with and without thoracic drainage (Groups TD+ and TD-, respectively) to determine the safety of the technique. The infusion led to a high steady-state concentration (Css) of 5.91 +/- 2.46 mg/mL in Group TD-. We then performed a placebo-controlled double-blind study on 16 patients to evaluate the analgesic effects of an interpleural infusion of 2% lidocaine using intravenous patient-controlled analgesia (PCA) with morphine and a visual analog scale score (VAS). In both studies an initial bolus of 3 mg/kg of 2% lidocaine was followed by an infusion of 1 mg.kg-1.h-1 for 48 h. The VAS score was slightly reduced after the bolus (6.6 +/- 1.0 vs 8.7 +/- 0.3; P < 0.05 vs the placebo group) but the cumulative doses of morphine were similar in both groups. There was a slight, but not sustained, improvement in pulmonary function test. In conclusion, interpleural analgesia by continuous infusion of lidocaine is poor after thoracotomy and may lead to blood levels in the toxic range.

Welte et al 1992

Effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy.

We have investigated the effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy. At the end of surgery, an interpleural catheter was inserted in 17 patients and, in a double-blind and randomized manner, either a bolus of morphine 2.5 mg interpleurally (i.p.) and normal saline i.v. (group I) or, as a control for systemic absorption, morphine 2.5 mg i.v. and i.p. saline (group II) was injected. After the initial bolus, a continuous infusion of morphine 0.5 mg h-1 i.p. and saline i.v. (group I) or morphine 0.5 mg i.v. and saline i.p. (group II) was maintained for 24 h. Postoperative pain was assessed by a visual analogue scale, a numerical rating scale and the McGill Pain Questionnaire. Pulmonary function was assessed by spirometry. Supplementary analgesics, side effects, degree of sedation, vital signs and chest tube drainage were recorded. All variables were assessed on the day before surgery and 1, 2, 3, 4, 5, 6 and 24 h and 7 days after surgery. Supplementary morphine was given upon request. There was no significant difference in any pain measure or postoperative pulmonary function variable between the groups. We conclude that, after thoracotomy, interpleural morphine does not provide superior analgesia or improve pulmonary function compared with systemic morphine.

Brockmeier et al 1994

Interpleural or thoracic epidural analgesia for pain after thoracotomy. A double blind study.

Brockmeier V, Moen H, Karlsson BR, Fjeld NB, Reiestad F, Steen PA.

Acta Anaesthesiologica Scandinavica 1994;38(4):317–21.

The analgetic effect of bupivacaine given epidurally or interpleurally after thoracotomy was investigated in a randomized, double blind, placebo controlled study. 32 patients with both an epidural and an interpleural catheter, were randomized to receive either interpleural or epidural analgesia. The interpleural group was given bupivacaine 5 mg.ml-1 with 5 microgram epinephrine as a 30 ml interpleural bolus, followed by a continuous infusion starting at a rate of 7 ml per hour and epidurally a bolus of 0.9% NaCl followed by a continuous infusion of 0.9% NaCl. The epidural group was given bupivacaine 3.75 mg.ml-1 with 5 microgram epinephrine as a 5 ml epidural bolus, followed by a continuous infusion starting at a rate of 5 ml per hour and interpleurally a bolus of 0.9% NaCl followed by a continuous infusion of 0.9% NaCl. The draining tubes were clamped during the injection of the interpleural bolus and 15 min afterwards. Adequacy of pain relief was evaluated with the Prins-Henry pain scale. Morphine requirement was registered, there was no difference between the groups in pain scores or need for additional morphine.

Ferrante et al 1991

Interpleural analgesia after thoracotomy.

Ferrante FM, Chan VW, Arthur GR, Rocco AG.

Anesthesia & Analgesia 1991;72(1):105–9.

We examined the effects of the following variables on interpleural analgesia after thoracotomy: addition of epinephrine to local anesthetic, thoracostomy drainage, two-catheter placement, and location of catheter tips. Twenty patients were randomized to have one catheter (paravertebral tip location) or two catheters (paravertebral and lateral thoracic wall tip locations). Interpleural catheters were sutured to the parietal pleura by the surgeon at time of wound closure. Patients were then randomly assigned to receive 20 mL of 0.5% bupivacaine with 1:200,000 epinephrine through the single catheter or 10 mL of 0.5% bupivacaine with or without 1:200,000 epinephrine through each of the two catheters while supine. Bupivacaine concentrations in whole blood and in thoracostomy drainage fluid were assayed by gas chromatography. Actual content of bupivacaine in the drainage fluid was calculated. Degree of analgesia was assessed by verbal numerical pain scores over the first 4 h and opioid demand thereafter. Addition of epinephrine to bupivacaine did not influence the degree of analgesia. Approximately 30%-40% of any administered dose of bupivacaine was lost via the thoracostomy tube over a 4-h period. There was no correlation between the true initial dose (100 mg minus thoracostomy drainage) and Cmax. Use of two catheters resulted in significantly less opioid requirements after an initial 8-h period. Failure to achieve adequate interpleural analgesia in postthoracotomy patients may be related to loss of anesthetic via thoracostomy drainage, presence of extravasated blood and tissue fluid in the pleural space, and possibly sequestration and channeling of flow of local anesthetic by restricted motion of an operated lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Elman et al 1993

Interpleural analgesia with bupivacaine following thoracotomy: ineffective results of a controlled study and pharmacokinetics.

Elman A, Debaene B, Magny-Metrot C, Murciano G.

Journal of Clinical Anesthesia 1993;5(2):118–21.

STUDY OBJECTIVE: To evaluate intrapleural analgesia with bupivacaine following partial pulmonary resection and to determine pharmacokinetic parameters of bupivacaine with epinephrine. DESIGN: Prospective, randomized study. SETTING: Thoracic surgical clinic of a university-affiliated general hospital. PATIENTS: Eighteen consecutive patients (13 men, 5 women) scheduled for pulmonary surgery by posterolateral thoracotomy. INTERVENTIONS: Bupivacaine was administered through an intrapleural catheter as a bolus dose of either 40 ml of 0.25% bupivacaine with epinephrine (0.5 mg per 100 ml of solution) (n = 10) or 20 ml of 0.5% bupivacaine with epinephrine (0.5 mg per 100 ml of solution) (n = 8) up to three times daily for a maximum time of 4 days. MEASUREMENTS AND MAIN RESULTS: Subjective evaluation of pain was performed using the visual analog scale (VAS) before and after each injection by response to spontaneous pain, coughing, deep breathing, and incision palpation. Maximum peak concentration (C Max) and maximum time to reach the peak concentration (T Max) were assessed after the first and last injections. Although VAS pain score decreased significantly, pain relief was not sufficient. C Max and T Max after the first and last injections were not significantly different between the two groups. In each group, C Max after the last injection was significantly higher than after the first injection. CONCLUSIONS: Intrapleural analgesia conducted with 40 ml of 0.25% bupivacaine with epinephrine or 20 ml of 0.5% bupivacaine with epinephrine was insufficient for pain, despite high plasma bupivacaine concentration.

Kambam et al 1989

Intrapleural analgesia for post-thoracotomy pain and blood levels of bupivacaine following intrapleural injection.

Kambam JR, Hammon J, Parris WC, Lupinetti FM.

Canadian Journal of Anaesthesia 1989;36(2):106–9.

An epidural type catheter was placed in the pleural space under direct vision before the closure of the chest in 24 patients who underwent thoracotomy for various types of lung or aortic surgery. All patients received intrapleural injections of 20 ml of 0.5 per cent bupivacaine with or without epinephrine as initial pain therapy. Patients also received subsequent doses of a similar volume of 0.375 per cent bupivacaine with epinephrine 1:200,000 up to four times a day for a maximum duration of seven days. Good pain relief was achieved in patients who underwent lateral and posterior thoracotomies. No pain relief was achieved in patients who underwent anterior thoracotomy or in patients in whom there was excessive bleeding in the pleural space. Bupivacaine blood concentrations were measured in 11 patients following the initial dose of 20 ml of 0.5 per cent bupivacaine (with epinephrine 1:200,000 in five of the 11 patients). The mean peak plasma concentration of bupivacaine when used with epinephrine was 0.32 +/- 0.02 microgram.ml-1. The mean peak plasma concentrations of bupivacaine when used without epinephrine was 1.28 +/- 0.48 microgram.ml-1. Our present data show that intrapleural analgesia is useful in the management of postoperative pain in patients who undergo thoracotomy. Our data also show that there is a significant decrease in peak plasma concentrations of bupivacaine when epinephrine is added to the solution (P less than 0.05).

Forty patients scheduled to undergo thoracotomy were randomly allocated to receive either transcutaneous electrical nerve stimulation with intramuscular papaveretum (20 patients) or intramuscular papaveretum alone (20 patients) for postoperative pain relief. Total intramuscular analgesic requirements in the first 24 hours, time to satisfactory transfer to oral analgesia, antiemetic requirements and length of stay in hospital postoperatively were noted. Peak expiratory flow rate was compared pre- and postoperatively in the two groups. Use of nerve stimulation did not significantly alter the requirements for analgesia although there was a reduction in postoperative nausea and vomiting in the nerve stimulation group. There was no difference between the two groups with respect to changes in peak expiratory flow rate.

Warfield et al 1985

The effect of transcutaneous electrical nerve stimulation on pain after thoracotomy.

Warfield CA, Stein JM, Frank HA.

Annals of Thoracic Surgery 1985;39(5):462–5.

The effect of postoperative transcutaneous electrical nerve stimulation (TENS) was evaluated in 24 patients in two randomly selected groups who underwent thoracotomy. The patients in one group received TENS through periincisional electrodes, and the remaining patients were treated with sham stimulator setups. The stimulators remained in place for 48 hours after operation. Subjective pain scores, duration of stay in the recovery room, tolerance to chest physical therapy, complaints of nausea, time to end of mechanical ventilation, and narcotic requirements were evaluated. Patients in the TENS group had significantly lower pain scores during the first 24 hours postoperatively (p = 0.014), shorter recovery room stays (p = 0.013), and better tolerance of chest physical therapy on both day 1 (p = 0.018) and day 2 (p = 0.006). No respiratory complications occurred in either group.

Bjordal et al 2003

AIM: We investigated the literature of randomised placebo-controlled trials to find out if transcutaneous electrical nerve stimulation (TENS) or acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) can reduce analgesic consumption after surgery. RESULTS: Subgroup analysis for adequate treatment (pulse frequency: 1-8Hz [ALTENS] or 25-150Hz [TENS], current intensity: "strong, definite, subnoxious, maximal tolerable" or above 15mA, and electrode placement in the incision area) were performed. Twenty-one randomised, placebo-controlled trials with a total of 1350 patients were identified. For all trials, the mean reduction in analgesic consumption after TENS/ALTENS was 26.5% (range -6 to +51%) better than placebo. Eleven of the trials compromising 964 patients, had reports which stated that a strong, subnoxious electrical stimulation with adequate frequency was administered. They reported a mean weighted reduction in analgesic consumption of 35.5% (range 14-51%) better than placebo. In nine trials without explicit confirmation of sufficient current intensity and adequate frequency, the mean weighted analgesic consumption was 4.1% (range -10 to +29%) in favour of active treatment. The difference in analgesic consumption was significantly (p=0.0002) in favour of adequate stimulation. The median frequencies used in trials with optimal treatment was 85Hz for TENS and 2Hz in the only trial that investigated ALTENS. CONCLUSION: TENS, administered with a strong, subnoxious intensity at an adequate frequency in the wound area, can significantly reduce analgesic consumption for postoperative pain.

Oncel et al 2002

OBJECTIVE: Few non-surgical conditions are more painful than rib fractures. There are a few methods for pain relief in patients with minor rib fractures. METHODS: We used a non-steroidal anti-inflammatory drug (NSAID, Naproxen sodium) and transcutaneous electrical nerve stimulator (TENS) to control pain of the patients with uncomplicated minor rib fractures. One hundred consecutive patients admitted to Kartal Education and Research Hospital Emergency Service, were randomized into four groups. The patients were assigned to one of the following pain treatments: NSAID, TENS, NSAID plus inactive TENS or placebo. The patients used NSAIDs and placebo four times a day and TENS twice a day for 3 days. All patients were asked to assess their pain level with a scoring system on days 0, 1 and 3. RESULTS: The most effective treatment was TENS on days 1 and 3 (P<0.05). Although NSAID and NSAID plus inactive TENS controlled pain better than placebo on day 1 (P<0.05), this superiority did not continue to day 3 (P>0.05). There was no difference between NSAID and NSAID plus inactive TENS in controlling pain on either days 1 or 3. CONCLUSION: We conclude that TENS was more effective than NSAID or placebo in patients with uncomplicated minor rib fractures, because of its prominent and admirable efficacy in reduction of pain.

Rakel et al 2003

J Pain 2003;4(8):455–64.This study tested the effectiveness of episodic transcutaneous electrical nerve stimulation (TENS) as a supplement to pharmacologic analgesia on pain with movement and at rest after abdominal surgery and evaluated whether its use during walking and vital capacity maneuvers enhances performance of these activities. TENS, with a modulated frequency, intensity as high as the subject could tolerate, and electrodes placed on either side and parallel to the incision, was compared to placebo TENS and pharmacologic analgesia alone (control) by using a crossover design. Self-report of pain intensity, walking function, and vital capacity were assessed on 33 subjects. TENS resulted in significantly less pain than the control during both walking (P <.5) and vital capacity activities (P <.1) and significantly less pain than placebo TENS during vital capacity (P <.01). TENS also produced significantly better gait speeds than the control (P <.05) and greater gait distances (P <.01) than the control and placebo TENS. Vital capacity and pain intensity at rest were not significantly different among the 3 treatments. These results suggest TENS reduces pain intensity during walking and deep breathing and increases walking function postoperatively when used as a supplement to pharmacologic analgesia. The lack of effect on pain at rest supports the hypothesis that TENS works through reducing hyperalgesia.

Despite receiving thoracic epidural analgesia, severe ipsilateral shoulder pain is common in patients after thoracotomy. We recruited 44 patients into a double-blinded randomized placebo-controlled study to investigate whether suprascapular nerve block would treat postthoracotomy shoulder pain effectively. All patients received a standard anesthetic with a midthoracic epidural. Thirty patients who experienced shoulder pain within 2 h of surgery were randomly assigned to receive a suprascapular nerve block with either 10 mL of 0.5% bupivacaine or 10 mL of 0.9% saline. Shoulder pain was assessed before nerve blockade, at 30 min, and then hourly for 6 h after the block using a visual analog scale (VAS) and a 5-point verbal ranking score (VRS). The incidence of shoulder pain before nerve block was 78%. There was no significant decrease in either VAS or VRS in the Bupivacaine group. These results suggest that this pain is unlikely to originate in the shoulder and lead us to question the role of a somatic afferent in referred visceral pain. We conclude that suprascapular nerve block does not treat ipsilateral shoulder pain after thoracotomy in patients with an effective thoracic epidural. IMPLICATIONS: This randomized, double-blinded, placebo-controlled trial showed that suprascapular nerve block does not treat the severe ipsilateral shoulder pain that patients experience after thoracotomy. This has implications for established theories of referred pain and indicates that this pain is unlikely to originate in the shoulder.

Sauls 2002

The use of ice for pain associated with chest tube removal.

Sauls J.

Pain Management Nursing 2002;3(2):44–52.

Every year more than 300,000 patients undergo cardiothoracic surgery, requiring placement of at least one chest tube. Removal of these chest tubes has been described as one of the worst intensive care unit experiences for these patients. Pain associated with chest tube removal (CTR) has been poorly controlled in many surgical patients. The purpose of this experimental study was to ascertain if the application of ice would decrease pain before, during, and after chest tube removal. Fifty postcardiac surgery patients were randomly assigned to two groups. The experimental group received ice therapy before CTR, whereas control subjects received a placebo. Pain intensity and pain distress were measured on a 0-10 numeric rating scale, and pain quality was measured using the McGill Pain Questionnaire-Short Form (MPQ-SF). Differences in pain intensity and pain distress between the experimental and control groups were not significant. A significant change in pain over time was noted in both groups, with pain intensity and distress being most severe during actual chest tube removal. Additionally, patients who received preprocedural pain medication did not differ in their levels of pain intensity or distress. Both groups used all the quality descriptors on the MPQ-SF for the sensory and affective components of pain, with cramping and gnawing as the most frequently chosen words. Continued research with larger samples is encouraged to further evaluate ice and other interventions that can be used to manage pain associated with CTR. Copyright 2002 by the American Society of Pain Management Nurses

Puntillo 1996

BACKGROUND: Moderate to severe pain associated with the removal of pleural chest tubes is poorly controlled with opioids. New methods are needed to manage the pain associated with this procedure. OBJECTIVES: To compare the effects of interpleural injections of 0.25% bupivacaine without epinephrine to those of normal saline on chest tube removal pain in cardiothoracic surgery patients. METHODS: A randomized, double-blind, placebo-controlled trial was used, with a repeated measures design. Pain intensity and distress were measured before, immediately after, and 1 hour after chest tube removal. Pain sensations and affect were evaluated immediately after chest tube removal. The experimental group (n = 21) received bupivacaine and the control group (n = 20) received normal saline. RESULTS: In both groups pain intensity and distress scores were significantly higher at the time of chest tube removal than immediately before or 1 hour after. No significant differences in pain intensity, distress, sensation, or affect scores were found between the two treatment groups. The 13 patients who received intramuscular ketorolac an average of 3.5 hours before the procedure, independent of the study design, had significantly lower pain intensity scores at the time of chest tube removal than the 26 who did not. CONCLUSIONS: These data demonstrate that chest tube removal pain is of moderate to severe intensity and that pleural chest tube injections of bupivacaine were not effective in decreasing chest tube removal pain. However, the decrease in pain associated with the administration of ketorolac warrants future study.